COVID-19 lockdown and the rate of central precocious puberty.

PURPOSE: The aim of our study was to compare the incidence of idiopathic central precocious puberty (CPP) in our highly specialized Endocrinological Center before and after the onset of COVID-19 lockdown; we also aimed to identify any potential difference between girls with CPP from the two different time periods. METHODS: We retrospectively analyzed the auxological profile of 49 girls with idiopathic CPP: 30 with pre-lockdown onset and 19 with post-lockdown onset of the disease. We collected patients' characteristics (medical history, physical examination, baseline and dynamic hormonal assessment, bone age, pelvic ultrasound) and compared them between the two groups. RESULTS: We registered an almost threefold increase in CPP incidence in the 2020-2021 period compared to the previous six years. In post-lockdown patients we found a trend for an earlier diagnosis in terms of both chronological age (p 0.0866) and days between the onset of first pubertal signs and diagnosis (p 0.0618). We also found that post-lockdown patients had a significantly lower hypothalamus-pituitary-gonadal axis activation (lower ∆LH% after GnRH test, p 0.0497), a significantly lower increase in bone age calculated at RUS with TW3 method (p 0.0438) and a significantly reduced ovarian activation in females (lower delta-4-androstenedione levels, p 0.0115). Interestingly, post-lockdown patients were born from mothers with an older age at menarche (p 0.0039). CONCLUSIONS: Besides confirming a significant increase in new diagnoses of CPP in the post-lockdown period, our findings among Post-lockdown girls also suggest a less progressive form of CPP and a stronger environmental influence compared to genetic background in determining the timing of pubertal onset.

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

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

The clinical value of serum-related indexes in differentiating simple premature thelarche from idiopathic central precocious puberty.

Objective: To explore the changes of serum-related indexes at different time points, so as to identify the critical time of converting from simple premature thelarche (PT) to idiopathic central precocious puberty (ICPP). Methods: This is a retrospective study. The subjects of the study were 50 girls with PT who were admitted to the Children's Hospital of Hebei Province from January 2019 to September 2020. The enrolled 50 children were divided into the conversion group(n=12) and the non-conversion group(n=38) according to whether PT was converted into ICPP during follow-up. Furthermore, the levels of serum-related indexes and uterine and ovarian volumes were compared after the diagnosis of PT. Results: The IGF-1 and IGFBP-3 levels of children in the conversion group began to change significantly from six months after the diagnosis, with statistically significant differences when compared with the levels of children at the initial diagnosis, three months and those of the non-conversion group at the same time points (p<0.05). The levels of vitamin-D, DHEA and leptin began to change significantly at nine months after the diagnosis (p<0.05). Besides, uterine and ovarian volumes in the conversion group began to increase significantly six months after the diagnosis, with statistically significant differences when compared with those in the non-conversion group (p<0.05). Conclusion: Findings in our study suggest that regular monitoring of vitamin-D, IGF-1, IGFBP-3, DHEA and leptin levels, and uterine and ovarian volumes can predict the conversion from PT to ICPP at an early stage.

EVALUATION OF OXIDATIVE STRESS MARKERS IN GIRLS WITH PREMATURE THELARCHE AND PRECOCIOUS PUBERTY.

Context: Oxidative products take part in various physiological processes and overproduction of oxidative products is involved in the etiology of many diseases. Objectives: We aimed to evaluate thiol-disulfide homeostasis (TDH); one of the oxidative stress parameters, in girls with premature thelarche (PT) and precocious puberty (PP). Design: This case-control study was conducted between January 2022 and July 2022. Subjects and Methods: TDH parameters, involving native thiol (NT), disulfide, and total thiol (TT), were evaluated in 39 girls with PT, 41 girls with PP and 46 healthy prepubertal girls. The correlations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) levels with the TDH parameters were determined and ROC curve analysis was performed. Results: NT, TT and NT/TT ratio were higher in the PT and PP groups compared to the control group (p<0.01). Disulfide/NT ratio and disulfide/TT ratio were lower in the PT and PP groups compared to the control group (p<0.05). All the TDH values did not statistically differ between the PP and PT group (p>0.05). There was a positive correlation between LH level, FSH level, and NT level, TT level, NT/TT ratio. The best parameter to discriminate PT or PT and control groups were NT and TT (p<0.01). Conclusion: TDH is altered in girls with PT and PP. NT and TT levels can be useful to discriminate prepubertal girls with lipomastia and girls with PP and PT in clinical practice. Further studies on larger cohorts of patients are required to clarify our results.

Pubertal mammary gland development is a key determinant of adult mammographic density.

Mammographic density refers to the radiological appearance of fibroglandular and adipose tissue on a mammogram of the breast. Women with relatively high mammographic density for their age and body mass index are at significantly higher risk for breast cancer. The association between mammographic density and breast cancer risk is well-established, however the molecular and cellular events that lead to the development of high mammographic density are yet to be elucidated. Puberty is a critical time for breast development, where endocrine and paracrine signalling drive development of the mammary gland epithelium, stroma, and adipose tissue. As the relative abundance of these cell types determines the radiological appearance of the adult breast, puberty should be considered as a key developmental stage in the establishment of mammographic density. Epidemiological studies have pointed to the significance of pubertal adipose tissue deposition, as well as timing of menarche and thelarche, on adult mammographic density and breast cancer risk. Activation of hypothalamic-pituitary axes during puberty combined with genetic and epigenetic molecular determinants, together with stromal fibroblasts, extracellular matrix, and immune signalling factors in the mammary gland, act in concert to drive breast development and the relative abundance of different cell types in the adult breast. Here, we discuss the key cellular and molecular mechanisms through which pubertal mammary gland development may affect adult mammographic density and cancer risk.

Metabolic characteristics and pathogenesis of precocious puberty in girls: the role of perfluorinated compounds.

BACKGROUND: Precocious puberty (PP) in girls is traditionally defined as the onset of breast development before the age of 8 years. The specific biomarkers of premature thelarche (PT) and central precocious puberty (CPP) girls are uncertain, and little is known about their metabolic characteristics driven by perfluorinated compounds (PFCs) and clinical phenotype. This study aimed to screen specific biomarkers of PT and CPP and elucidate their underlying pathogenesis. The relationships of clinical phenotype-serum PFCs-metabolic characteristics were also explored to reveal the relationship between PFCs and the occurrence and development of PT and CPP. METHODS: Nuclear magnetic resonance (NMR)-based cross-metabolomics strategy was performed on serum from 146 PP (including 30 CPP, 40 PT, and 76 unspecified PP) girls and 64 healthy girls (including 36 prepubertal and 28 adolescent). Specific biomarkers were screened by the uni- and multivariate statistical analyses. The relationships between serum PFCs and clinical phenotype were performed by correlation analysis and weighted gene co-expression network analysis to explore the link of clinical phenotype-PFCs-metabolic characteristics in PT and CPP. RESULTS: The disordered trend of pyruvate and butyrate metabolisms (metabolites mapped as formate, ethanol, and 3-hydroxybutyrate) were shared and kept almost consistent in PT and CPP. Eight and eleven specific biomarkers were screened for PT and CPP, respectively. The area under curve of specific biomarker combination was 0.721 in CPP vs. prepubertal, 0.972 in PT vs. prepubertal, 0.646 in CPP vs. prepubertal integrated adolescent, and 0.822 in PT vs. prepubertal integrated adolescent, respectively. Perfluoro-n-heptanoic acid and perfluoro-n-hexanoic acid were statistically different between PT and CPP. Estradiol and prolactin were significantly correlated with PFCs in CPP and PT. Clinical phenotypes and PFCs drive the metabolic characteristics and cause metabolic disturbances in CPP and PT. CONCLUSIONS: The elevation of formate, ethanol, and 3-hydroxybutyrate may serve as the early diagnostic indicator for PP in girls. But the stratification of PP still needs to be further determined based on the specific biomarkers. Specific biomarkers of CPP and PT exhibited good sensitivity and can facilitate the classification diagnosis of CPP and PT. PFC exposure is associated with endocrine homeostasis imbalance. PFC exposure and/or endocrine disturbance directly or indirectly drive metabolic changes and form overall metabolic network perturbations in CPP and PT.

Differential diagnosis of precocious puberty in girls during the COVID-19 pandemic: a pilot study.

BACKGROUND: To investigate the differential diagnosis of girls aged 6 to 8 years with idiopathic premature thelarche (IPT) and central precocious puberty (CPP) during the COVID-19 pandemic. We explored predicted adult height (PAH) discrepancy to guide appropriate diagnosis and treatment. METHODS: From January 2020 to December 2021, Chinese girls aged 6 to 8 years with precocious puberty were recruited. They were divided into IPT and CPP groups. Clinical characteristics, including height, weight, body mass index (BMI), basal luteinizing hormone (LH), oestradiol, uterine length and volume, follicle numbers (d > 4 mm) and bone age (BA) were recorded. We analysed differential diagnosis and PAH discrepancy in both groups. Binary logistic regression analysis was used to explore risk factors for CPP, and receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of related indexes. RESULTS: Sixty patients, including 40 girls with IPT and 20 girls with CPP, were recruited. The prevalence of overweight and obesity in the entire cohort was 25% (15/60) and was significantly higher in IPT than CPP, 32.5% (13/40) vs. 10% (2/20), respectively (P=0.045). There were significant differences in LH, uterine volume, follicle numbers and BA (P<0.05). The impaired PAH of IPT and CPP was 0.01 ± 1.19 SD and 0.62 ± 0.94 SD with significant differences (P=0.047). Logistic regression analysis showed that LH and follicle numbers were independent risk factors for CPP. The ROC curve showed that the area under the curve (AUC) of LH and follicle numbers were 0.823 and 0.697. The sensitivity and specificity of LH with a cut off of 0.285 IU/L were 78.9% and 77.8%. The sensitivity and specificity of follicle numbers with a cut off of 3.5 were 89.5% and 52.8%. CONCLUSION: The prevalence of overweight and obesity in 6- to 8-year-old girls with precocious puberty was high. Auxological data should not be used in the differential diagnosis of IPT and CPP. Basal LH above 0.285 IU/L and follicle numbers greater than 4 were important features suggestive of CPP. PAH was impaired in individuals with CPP, but it was not impaired in individuals with IPT.

Leptin, ghrelin, nesfatin-1, and orexin-A plasma levels in girls with premature thelarche.

PURPOSE: Reducing the mean age of puberty onset in recent years has crucial public health, clinical, and social implications. This study aimed to evaluate the serum levels of appetite-related peptides (leptin, ghrelin, nesfatin-1, and orexin-A) and anthropometric data in girls with premature thelarche (PT). METHODS: We enrolled 44 girls aged 4-8 years diagnosed with PT and 33 age-matched healthy girls as controls. The demographic data of the girls were obtained using a questionnaire. Anthropometric data were measured and fasting blood samples were collected. RESULTS: Body weight, height, body mass index (BMI), body fat mass, and basal metabolic rate (BMR) were higher in the PT group than in the control group (p < 0.05). Serum leptin (p < 0.001), nesfatin-1 (p = 0.001), and orxein-A (p < 0.001) levels were significantly higher in the PT group than in healthy controls. However, there were no significant differences in the serum ghrelin levels between the groups (p > 0.05). The results of multivariate logistic regression revealed that serum leptin level (OR (95% CI): 42.0 (10.91, 173.06), p < 0.001), orexin-A (OR (95% CI): 1.14 (1.04, 1.24), p = 0.006), and BMI for age z-score (OR (95% CI): 6.97 (1.47, 33.4), p = 0.014) elevated the risk of incidence of PT at 4-8 girls. CONCLUSION: These results suggest that in addition to serum leptin levels, serum orexin-A and nesaftin-1 can take part in the initiation of PT. Few studies have investigated the relationship between nesfatin-1 and orexin-A levels and age at onset of puberty; hence, it should be a subject for future studies.

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

BACKGROUND: 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 US 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 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. RESULTS: Early 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. CONCLUSIONS: Associations 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.

Pubertal timing and breast cancer risk in the Sister Study cohort.

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.

Reproductive hormones during pubertal transition in girls with transient Thelarche.

CONTEXT: Transient thelarche (TT), that is, the appearance, regression and subsequent reappearance of breast buds, is a frequent phenomenon, but little is known about pubertal transition in these girls. OBJECTIVE: To describe pubertal progression, growth, genotypes, reproductive hormones and growth factors in girls with TT compared to those who do not present TT (non-TT). DESIGN: Retrospective analysis of a longitudinal population-based study. PATIENTS OR OTHER PARTICIPANTS: Girls (n = 508) of the Chilean Growth and Obesity cohort. MEASUREMENTS: Pubertal progression, reproductive hormones, follicle stimulating hormone (FSH) beta subunit/FSH receptor gene single nucleotide polymorphisms and growth. RESULTS: Thirty-seven girls (7.3%) were presented TT. These girls entered puberty by pubarche more frequently (51%) than girls with normal progression (non-TT; n = 471; 23%, P = .005). Girls with TT who were under 8 years old had lower androgens, anti-Müllerian hormone (AMH), luteinizing hormone (LH) and oestradiol (all P < .05) than older girls with TT. At the time of Tanner breast stage 2 (B2), girls with TT had higher androgens, LH, FSH, IGF1, LH, insulin and oestradiol (P < .01) than at the time of TT. TT girls were older at B2 (10.3 ± 1.1 vs. 9.2 ± 1.2 years, P < .001) and menarche (12.3 ± 0.8 vs. 12.0 ± 1.0 years, P = .040) than their counterparts (non-TT). No differences in anthropometric variables or FSHB/FSHR genotypes were detected. CONCLUSION: Transient thelarche is a frequent phenomenon that does not appear to be mediated by hypothalamic-pituitary-gonadal axis activation or by adiposity. Hormonal differences between earlier TT and later TT suggest that their mechanisms are different.

Basal serum luteinising hormone cut-off, and its utility and cost-effectiveness for aiding the diagnosis of the onset of puberty in girls with early stages of breast development.

OBJECTIVE: To determine basal and gonadotrophin-releasing hormone analogue (GnRHa)-stimulated peak luteinising hormone (LH) cut-offs to diagnose onset of early or normal puberty in girls with each Tanner stage of breast (II and III). DESIGN, PATIENTS AND MEASUREMENTS: A retrospective study of 601 girls with breast onset before 8 years of age who underwent GnRHa test was conducted. Patients were categorized as CPP and premature thelarche. Each group was divided into two subgroups; Tanner II and III. Cost-effectiveness analysis was performed. RESULTS: In comparison with basal LH cut-off of 0.3 IU/L, basal LH cut-off of 0.2 IU/L had comparable specificity (Tanner II: 98.0% vs 94.8%, Tanner III: 98.8% vs 93.8%), but greater sensitivity (Tanner II: 28.3% vs 41.7%, Tanner III: 45.2% vs 59.3%). Specificity of basal LH cut-off of 0.2 IU/L was not inferior to that of the traditionally used peak LH of 5 IU/L. Using basal LH cut-off of 0.2 IU/L followed by GnRHa test in girls with negative basal LH was more cost-saving when compared with using the cut-off of 0.3 IU/L. Moreover, using basal LH cut-off of 0.2 IU/L followed by GnRHa test provided a cost reduction when compared with performing GnRHa test in all patients. CONCLUSIONS: Basal serum LH cut-off of 0.2 IU/L could be a simple and cost-saving tool for initial diagnosis of onset of early or normal puberty in girls with Tanner II and III before proceeding to GnRH testing.

Greater adherence to a Mediterranean-like diet is associated with later breast development and menarche in peripubertal girls.

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.

Factors affecting bone maturation in Chinese girls aged 4-8 years with isolated premature thelarche.

BACKGROUND: In isolated premature thelarche (IPT) girls, bone age (BA) is considered consistent with chronological age. However, some IPT girls confirmed by gonadotropin-releasing hormone (GnRH) stimulation test could show another trend. We analysed BA and possible potentiating factors in a selected group of girls aged 4-8 years with IPT. METHODS: IPT girls confirmed by GnRH stimulation test aged 4-8 years hospitalized from January 2015 to April 2018 at Shenzhen Children's Hospital were included in this retrospective study. They were divided into two groups with advanced BA of 2 years as the cut-off. Body mass index (BMI) and hormone levels were the main outcome measures, and regression analysis was used to identify independent risk factors. IPT girls were divided into subgroups according to the levels of BMI standard deviation score (SDS), insulin-like growth factor-1 (IGF-1) SDS and dehydroepiandrosterone sulfate (DHEAS) SDS for comparisons of advanced BA. RESULTS: Overall, 423 subjects were included and classified into the advanced BA group (48.7%, n = 206) and control group (51.3%, n = 217). The advanced BA group had significantly higher BMI SDS, serum DHEAS SDS, IGF-1 SDS, androstenedione and fasting insulin and significantly lower sex hormone binding globulin (all p < 0.001). Serum IGF-1 SDS (OR = 1.926, p<0.001), BMI SDS (OR = 1.427, p = 0.001) and DHEAS SDS (OR = 1.131, p = 0.005) were independent risk factors for significantly advanced BA. In the multiple linear regression model, serum IGF-1 SDS, BMI SDS and DHEAS SDS were the strongest predictors of advanced BA, accounting for 19.3% of the variance. According to BMI, 423 patients were classified into three groups: normal weight (56.03%, n = 237), overweight (19.15%, n = 81) and obesity (24.82%, n = 105). The proportion of advanced BA in obesity group was significantly higher than those of normal weight and overweight groups (χ2 = 18.088, p<0.001). In the subgroup with normal weight, higher serum IGF-1 SDS (p = 0.009) and DHEAS SDS (p = 0.003) affected BA advancement independent of BMI SDS. CONCLUSIONS: Girls with IPT confirmed by GnRH stimulation test aged 4-8 years might have significantly advanced BA. Obesity was highly associated with advanced BA. Age-specific serum IGF-1 SDS and DHEAS SDS were risk factors for BA advancement independent of BMI.

Integrated Approach to Evaluate the Association between Exposure to Pesticides and Idiopathic Premature Thelarche in Girls: The PEACH Project.

Several pesticides are recognized as endocrine-disrupting chemicals (EDCs) since they can interfere with the dysregulation of sexual, thyroid and neuro-endocrine hormones. Children are particularly vulnerable to the adverse effects of EDCs due to their developmental stage, peculiar lifestyle and dietary habits. In this context, the exposure to pesticides represents an important risk factor associated with early development. This study deals with the possible association between exposure to pesticides and idiopathic premature thelarche in girls from areas of intensive agriculture practice in the Centre of Italy. An integrated approach was set up, including: (i) a case-control study on girls with idiopathic premature thelarche; (ii) the evaluation of multiple pesticides exposure in girls; (iii) the evaluation of multiple pesticides in food; (iv) the dietary intake of pesticide residues; (v) the assessment of toxicological effects of widely used pesticides by in vitro model. Data integration will provide an estimate of the predictive risk of potential effects on girls' health, linked to dietary intake.

A 10-Month-Old Infant Presenting With Signs of Precocious Puberty Secondary to a Sclerosing Stromal Tumor of the Ovary in the Absence of Hormonal Elevation.

Precocious puberty in an infant is an alarming and infrequent finding, making the differential diagnosis difficult for practitioners. Precocious puberty secondary to a sclerosing stromal tumor (SST) of the ovary is rare. We present a case of a child that began precocious puberty at 3 months of age including development of breast buds, pubic hair, growth spurt, and menarche 5 days prior to presenting to pediatric endocrinology at 10 months. She underwent right salpingo-oophorectomy which demonstrated a soft tissue mass occupying almost the entire ovary with a tan-pink fleshy cut surface. Histological examination confirmed a variant of SST. This case represents an extremely young onset of precocious puberty secondary to a variant of SST without hormonal elevation.

The prevalence of premature thelarche in girls and gynecomastia in boys and the associated factors in children in Southern China.

BACKGROUND: To investigate the prevalence and risk factors of premature thelarche (PT) in girls and gynecomastia (GM) in boys in Southern China. METHODS: We conducted a cross-sectional study of preschool children across 9 cities in Zhejiang province. A total of 6273 children in the age-group of 2-7 years were recruited from January 2014 to March 2015. Relevant information was collected from mothers through face-to-face interviews. Logistic regression models were used to examine the correlates of PT and GM. Odds ratios (ORs) with 95% confidence intervals (CIs) are reported. RESULTS: The prevalence of PT among girls was 4.8% and that of GM among boys was 0.8%. One hundred girls were diagnosed with PT before the age of 2 years; 69 (69.0%) of these girls experienced spontaneous resolution of PT. Twenty-four boys were diagnosed with GM before the age of 2 years; 10 (41.7%) of these experienced spontaneous resolution of GM. Children borne of mothers with early onset of menarche and those belonging to high-income families were at a higher risk of premature breast development. Greater consumption of eggs was associated with premature breast development in early childhood. CONCLUSIONS: Socioeconomic status of family, early onset of menarche in mother, and consumption of eggs were strongly associated with premature breast development in early childhood.

No association between estrogen receptor gene polymorphisms and premature thelarche in girls.

OBJECTIVE: Premature thelarche (PT) is a benign, nonprogressive condition defined as isolated breast development. While the pathophysiology of PT remains unclear, increased sensitivity to estrogen may cause PT. The aim of this study was to investigate the association between polymorphisms in the estrogen receptor alpha (ERα) gene and PT in girls. METHODS: In this case-control study, we examined 96 girls referred for early breast development (before the age of 8 years). The control group included healthy Korean females with normal pubertal progression. Anthropometric and hormonal parameters were measured and PvuII and XbaI ERα gene polymorphisms were evaluated by PCR. Out of the 96 girls, all coding exon and exon-intron boundaries of ERα were sequenced from the DNA of 46 girls. RESULTS: There was no significant difference in the distribution of PvuII and XbaI polymorphisms between patients and controls. However, the carriers of XbaI polymorphisms had more advanced Tanner stage than did the non-carriers. Also, four ERα gene polymorphisms were previously identified, but these polymorphisms had no clinical significance. CONCLUSION: No association was found between the ERα gene polymorphisms and PT in girls. However, XbaI polymorphisms may contribute to early breast budding.

Associations Between Maternal Pregravid Obesity and Gestational Diabetes and the Timing of Pubarche in Daughters.

We investigated whether in utero exposure to maternal pregravid obesity and/or gestational diabetes mellitus (GDM) was associated with early puberty in girls. We used data from a longitudinal study of 421 mother-daughter pairs enrolled in an integrated health services organization, Kaiser Permanente Northern California (2005-2012). Girls aged 6-8 years were followed annually through ages 12-14 years. Onset of puberty was assessed using study clinic-based Tanner staging. We examined associations of self-reported pregravid obesity and maternal GDM with timing of the daughter's transition to pubertal maturation stage 2 or above for development of breasts and pubic hair, using accelerated failure time regression models with interval censoring to estimate time ratios and hazard ratios and corresponding 95% confidence intervals. Maternal obesity (pregravid body mass index (BMI; weight (kg)/height (m)(2)) ≥30) was associated with a daughter's earlier transition to breast and pubic hair stage 2+ in comparison with girls whose mothers had pregravid BMI <25. These associations were attenuated and not statistically significant after adjustment for covariates. Girls whose mothers had both pregravid BMI ≥25 and GDM were at higher risk of an earlier transition to pubic hair stage 2+ than those whose mothers had neither condition (adjusted time ratio = 0.89, 95% confidence interval: 0.83, 0.96; hazard ratio = 2.97, 95% confidence interval: 1.52, 5.83). These findings suggest that exposure to maternal obesity and hyperglycemia places girls at higher risk of earlier pubarche.

Father's death does not affect growth and maturation but hinders reproduction: evidence from adolescent girls in post-war Estonia.

The popular concept of predictive-adaptive responses poses that girls growing up without a father present in the family mature and start reproduction earlier because the father's absence is a cue for environmental harshness and uncertainty that favours switching to a precocious life-history strategy. Most studies supporting this concept have been performed in situations where the father's absence is caused by divorce or abandonment. Using a dataset of Estonian adolescent girls who had lost their fathers over the period of World War II, we show that father's death did not affect the rate of pubertal maturation (assessed on the basis of development of breasts and axillary hair) or growth. Father's death did not affect the age of first birth but, contrary to predictions, reduced lifetime reproductive success. Our findings thus do not support the concept of predictive-adaptive responses and suggest that alternative explanations for covariation between fatherlessness and early maturation are required.