Pubertal Breast Development Research Articles

Early-life exposures and age at thelarche in the Sister Study cohort

BackgroundEarly age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974.MethodsBreast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood.ResultsEarly thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche.ConclusionsAssociations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

Early-life Exposures and Age at Breast Development in the Sister Study Cohort

Abstract Purpose: Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a U.S. cohort of women born between 1928 and 1974. Methods: Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003–2009 (N = 50,884). At enrollment, participants reported their age at thelarche, which we categorized as early (≤10 years), average (11–13 years), and late (≥14 years), as well as information on early-life exposures. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche relative to average age at thelarche using polytomous logistic regression for each early-life exposure, adjusted for birth cohort, race/ethnicity and family income level in childhood. We examined modification by birth cohort, race/ethnicity, family income, relative weight at age 10, and extent of breast cancer family history through stratification. Results: Early thelarche was more common in recent birth cohorts and among non-Hispanic Black and Hispanic women. Early thelarche (≤10 years) was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI, 1.09–1.43), maternal diethylstilbestrol (DES) use (OR = 1.23, 95% CI, 1.04–1.45), maternal smoking during pregnancy (OR = 1.20, 95% CI, 1.13–1.27), and young maternal age (OR 1.30, 95% CI, 1.16–1.47 for &amp;lt;20 vs 25–29 years). Being firstborn was also associated with early thelarche (OR = 1.25, 95% CI, 1.17–1.33). Low birthweight (&amp;lt;2500 vs 2500–3999g) was suggestively associated with both early (OR = 1.06, 95% CI, 0.96–1.17) and late (OR = 1.15, 95% CI, 1.05–1.25) thelarche, as was use of soy formula in infancy (Early: OR = 1.10, 95% CI, 0.93–1.30; Late: OR = 1.07, 95% CI, 0.92–1.25). Patterns were generally similar across strata of modifiers of interest. Conclusion: Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment may influence breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

Ultrasound assessment of pubertal breast development in girls: intra- and interobserver agreement

Clinical assessment of pubertal breast development using Tanner staging is subjective. This has led to the introduction of ultrasound (US), aiming for a more objective analysis. However, information regarding its reliability is lacking. To examine intra- and interobserver agreement of breast maturity staging using US and to examine the precision of direct measurements of the gland. Fifty-seven healthy girls (mean age: 10.9years, range: 6.1 to 15.9years) were examined independently by two observers using US of the left breast to score the glandular maturity stage on a 0-5 scale, and to measure the depth and diameter. One observer repeated the examination after 20 to 35min to assess intra-observer agreement. Cohen's kappa with linear weights was used to examine intra- and interobserver agreement of the US staging, while the measurement precision was analyzed using Bland-Altman plots and 95% limits of agreement. The agreement of US staging on a 0-5 scale was very good (kappa 0.84; 95% confidence interval [CI] 0.78-0.91) for intra-observer observation and good (kappa 0.71; 95% CI 0.62-0.80) for interobserver observation. Measurements of glandular depth and diameter were unbiased for a single observer, but the variances were large both within and between observers. US using a scale from 0 to 5 is a reliable method to stage the development of glandular breast tissue during puberty in healthy girls. Measurements of glandular depth and diameter were found to be imprecise.

Urinary bisphenol A levels in Turkish girls with premature thelarche.

There is a growing concern over the timing of pubertal breast development and its possible association with exposure to endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA). BPA is abundantly used to harden plastics. The aim of this study was to investigate the relation between premature thelarche (PT) and BPA by comparing the urinary BPA levels of PT girls with those of healthy subjects. Twenty-five newly diagnosed nonobese PT subjects (aged 4-8 years) who were admitted to the Pediatric Endocrinology Department at Akdeniz University were recruited. The control group composed of 25 age-matched girls without PT and other endocrine disorders. Urinary BPA levels were measured by high pressure liquid chromatography. The median urinary concentrations of BPA were found to be significantly higher in the PT group compared to the healthy control group (3.2 vs. 1.62 μg/g creatinine, p < 0.05). We observed a weak positive correlation between uterus volume and urinary BPA levels. There was a weak correlation between estradiol and urinary BPA levels ( r = 0.166; p = 0.37); and luteinizing hormone and urinary BPA levels ( r = 0.291; p = 0.08) of PT girls. Our results suggest that exposure to BPA might be one of the underlying factors of early breast development in prepubertal girls and EDCs may be considered as one of the etiological factors in the development of PT.

Pubertal breast development in primary school girls in Sokoto, North-western Nigeria

Background. There is wide variation in normal pubertal timing among various populations. Objectives. To determine the mean age of pubertal stages of breast development and menarche, and the influence of nutrition and ethnicity on pubertal onset in primary school girls in Sokoto, North-Western Nigeria. Methods. A cross-sectional study using a multistage random sampling design was conducted on 994 primary school girls in grades 3 - 6. Weight and height measurements and Tanner breast staging were done. Body mass index (BMI) was calculated, and a BMI-for-age percentile was used to categorise nutritional status. There were four major ethnic groups. P≤0.05 was taken as showing statistical significance. Results. The participants’ mean age was 10.23 years (standard deviation (SD) 1.70, range 6 - 15 years). Of the 994 girls, 628 (63.2%) were pre-pubertal, and 366 (36.8%) were pubertal. Of the latter, 158 (15.9%) were in breast stage 2, while 112 (11.3%), 70 (7.0%) and 26 (2.6%) were in breast stages 3, 4 and 5, respectively. The mean ages (SD; range) of pubertal onset and menarche were 10.50 (1.33; 8 - 13), and 12.67 (1.65; 11 - 15), years, respectively. The overnourished (overweight/obese) and Igbo ethnic group girls had early-normal pubertal onset ( p =0.006 and p =0.001, respectively). Conclusion. The mean ages of Tanner breast stages 1 - 5 and menarcheal age of girls in Sokoto, North-Western Nigeria, were within the age ranges reported worldwide. Pubertal onset was influenced by nutrition.

Longitudinal assessment of circulating insulin-like peptide 3 levels in healthy peripubertal girls

To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to puberty as well as its relation to other reproductive hormones. Population-based cohort study. Not applicable. Healthy peripubertal girls (n = 10) examined every 6 months; total number of examinations was 84; median (range) per girl: 9 (4-10), including staging of pubertal breast development and blood samples. None. Serum levels of INSL3, inhibin B, E2, antimüllerian hormone, LH, and FSH (validated immunoassays), and T and androstenedione (liquid chromatography-tandem mass spectrometry). Serum levels of INSL3 varied considerably between girls (range, 0.01-0.27 ng/mL) and within each girl as puberty progressed; intraindividual variation, median (range) 102% (65%-143%). Insulin-like peptide 3 increased in late puberty (B1 to B4+B5); geometric mean 0.03 ng/mL to 0.15 ng/mL. Insulin-like peptide 3 levels reflected markers of large follicles (T, androstendione, inhibin B, and E2) better than markers of small follicles (antimüllerian hormone), and INSL3 staining was localized in theca interna cells of antral follicles. Insulin-like peptide 3 increased in late puberty, albeit inter- and intraindividual variations were substantial. Immunohistochemistry and intraindividual variation, as well as relations to other ovarian hormones, reveal that INSL3 in girls is a unique and specific marker of theca cells surrounding antral follicles. The potential clinical use of INSL3 for evaluation of ovarian function in girls remains to be elucidated.

Dietary Soy Effects on Mammary Gland Development during the Pubertal Transition in Nonhuman Primates

While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for approximately 4.5 years: (i) casein/lactalbumin (CL, n = 12, as control) or (ii) soy protein isolate with a human equivalent dose of 120 mg/d isoflavones (SOY, n = 17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of four postmenarchal ultrasound measurements (P < 0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P < 0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P < 0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood.

Primary amenorrhea in a young Polish woman with complete androgen insensitivity syndrome and Sertoli–Leydig cell tumor: Identification of a new androgen receptor gene mutation and evidence of aromatase hyperactivity and apoptosis dysregulation within the tumor

Primary amenorrhea in 46,XY females can be due to complete androgen insensitivity syndrome (CAIS), pure gonadal dysgenesis, 17β-hydroxysteroid dehydrogenase deficiency, or mixed gonadal dysgenesis. The present paper describes a new de novo non-sense mutation in exon 1 (K141Z) of the androgen receptor gene (AR) and the expression in CAIS testis of aromatase, estrogen receptors, as well as proliferation- and apoptosis-associated proteins. CAIS is a rare disease characterized by absent virilization in 46,XY individuals and the development of a female phenotype despite normal or even elevated androgen levels. CAIS is usually caused by a mutation in AR, which leads to organ resistance to androgens. Testicular tumors such as Sertoli–Leydig cell tumor often develop in patients with CAIS. The immunohistochemical findings in the testes of our CAIS patient suggest that the high expression of aromatase and other molecular changes in the testis may be responsible for pubertal breast development and the increased risk of testicular tumor.

Age at menarche and age of onset of pubertal characteristics in 6-14-year-old girls from the Province of L'Aquila (Abruzzo, Italy).

The present study is part of a research project on growth models of children in an area of central-southern Italy. It analyzes the phases of pubertal breast development (BD) in 397 girls, pubic hair development (PHD) in 399 girls, and menarche in 583 girls from 6-14 years old. The status quo method was used to evaluate the age at menarche. Probit analysis was used to analyze the data for all three variables. The onset of BD and PHD (Tanner stage 2) occurs at age 7 in 6.1% of girls. Passage to stage 3 of one or both secondary sexual characteristics occurs at age 10 in 8.5% of girls. Comparison with data from the United States shows higher percentages of American white girls in stage 2 (or greater) of both characteristics at any age. The mean (median) age of onset (Tanner stage 2) of BD or PHD or both of them is 9.96 years. The passage to stage 3 occurs at age 12.36 for BD (95% confidence interval: 1.36 years) and at age 12.10 for PHD (95% confidence interval: 0.51 years). The mean age at menarche is 12.55 years, in general agreement with other values found in Italy. Sexual maturation at any considered stage for both pubertal characteristics is generally in line with literature data concerning other Mediterranean and industrialized countries or countries in which the demographic transition is in an advanced phase. It does not show a significant earlier onset. The evidence emerging from the general project suggests that the secular trend is still in progress in this region of Italy.

Difficulties with age estimation of internet images of south‐east Asian girls

AbstractCommunity paediatricians are increasingly asked to provide expert opinion on internet child pornography related to ‘sex tourism’, mostly in south‐east Asian countries. The girls involved are often prepubertal, and the main legal question is to establish whether they are under 13 years of age. This paper provides a review of the literature related to this question. Although there are limited data of age of menarche from the countries at risk of ‘sex tourism’, one recent study from the Philippines showed that the mean age of menarche was similar to the mean age of British girls born between 1982 and 1986. There are no data in the above countries on the early pubertal changes in breast development, but studies from India and China suggested that these might be more prolonged than for British girls. In particular, the interval between B2 stage (early pubertal breast development) and menarche was nearly 3 years in these developing countries, compared with 2 years for the British girls. Maternal malnutrition and girls small for gestational age at birth resulted in an earlier menarche, while chronic malnutrition, severe enough to cause stunting in preschool years, caused a delay in menarche. Taking into account information from the existing studies, we estimated that 97.5% of south‐east Asian girls will show pubertal changes of B2 stage by the age of 13.7 years. Copyright © 2003 John Wiley &amp; Sons, Ltd.

Breast contact thermography for differentiation between premature thelarche and true precocious puberty.

Breast contact thermography was used to differentiate between premature thelarche and true precocious puberty. The technique was applied to 10 girls with premature thelarche, 12 with precocious puberty and 105 controls (Tanner B1-5). In controls, the scores attributed to the maturative thermographic signs correlated with breast development stages. In premature thelarche thermographic signs of vascularization were always absent, while in precocious puberty they were always observed, although in some cases unilaterally. The thermographic index (higher total score between the two breasts) ranged from 0 to 3 in girls with premature thelarche and from 4 to 10 in girls with precocious puberty. The thermographic pattern in premature thelarche was similar to that in prepubertal girls and did not progress in two girls who were repeatedly examined. We emphasize the useful role of contact thermography in evaluating pubertal breast development and in differentiating between premature thelarche and true precocious puberty.

BREAST CONTACT THERMOGRAPHY IN DIFFERENTIAL DIAGNOSIS OF PREMATURE THELARCHE AND PRECOCIOUS PUBERTY

In order to contribute to the differential diagnosis between idiopathic Premature Thelarche (PT)and true Precocious Puberty (PP) we performed Breast Contact Thermography (BCT, cholesteric liquid crystal plates) in 13 girls with PT and 12 with PP (previously diagnosed) and in 105 control girls (Tanner's 81-5). We evaluated the 4 principal components (fundus, vascularization, nipple and periareolar heat changes). Arbitrary gradual scores (0,1,2…) were attributed to the maturative signs. A Thermographic Index (TI= sum of the 4 scores of a single breast) and the higher TI (hTI = between the 2 breasts of single girls) were calculated.Results: in controls, single scores, TI and hTI had a positive correlation (r, p<0.001) with B stages. In PT, all signs of vascularization were always (100%) absent, while in PP they were always present, although in some cases monolaterally. The TI of PT was not different from B1 girls and significantly lower (p<0.001) than PP girls and B>1 controls. The hTI ranged from 0 to 3 in PT, from 4 to 13 in PP girls.We conclude that low hTI (≤ 3)and no signs of vascularization indicate PT, while vascular hyperthermia and hTI ≥ 4 indicate PP. We emphasize the useful diagnostic aid of the noninvasive imaging technique of BCT in evaluating the pathophysiology of pubertal breast development.

Male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency.

This is the first report of a male with 17alpha-hydroxylase deficiency resulting in male pseudohermaphroditism, ambiguous external genitalia, absence of male secondary sexual characteristics, and gynecomastia at puberty. Diagnosis was based on extensive studies of steroid metabolism including the following: low urinary excretion of 17-ketosteroids and 17-hydroxycorticoids which did not increase after ACTH; no response of very low plasma testosterone and dehydroepiandrosterone to adrenocorticotropin (ACTH) or chorionic gonadotropin; and low urinary aldosterone and plasma renin which increased after dexamethasone. Secretion rates of 17-hydroxylated steroids, cortisol (F) and 11-desoxycortisol (S), were very low while desoxycorticosterone (DOC) and corticosterone (B) secretion rates were increased sevenfold. Results expressed as milligrams per meter squared per day were as follows: F, 1.3; S, 0.023; DOC, 0.35; and B, 16 (mean normal values were F, 7.5; S, 0.26; DOC, 0.055, and B, 2.2). Plasma gonadotropins were markedly increased (FSH, 106; LH, 364 mIU/ml). Testicular biopsies revealed interstitial-cell hyperplasia and early spermatogenesis. Karyotype was 46/XY. Pedigree showed no other affected member. At laparotomy ovaries, uterus, and fallopian tubes were absent, vas deferens was incomplete, and prostate was present. External genitalia consisted of small phallus, bifid scrotum, third-degree hypospadias, and small vagina. At puberty there was no growth of body hair or phallic enlargement. Biopsy of marked gynecomastia showed both ducts and acini. Testosterone administration produced virilization. Sexual ambiguity demonstrates strong dependence of external genitalia on androgens for male differentiation. Suppression of Müllerian structures occurred despite female levels of testosterone indicating this step in male differentiation is not testosterone dependent. Pubertal breast development in this male supports the concept of femaleness during ontogeny unless counteracted by male factors. Diagnosis of other adrenocortical enzymatic deficiencies is excluded by the steroidal studies. The clinical response to testosterone excludes testicular feminization. Deficiency of 17-hydroxylation must be added to the cause of male pseudohermaphroditism.