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Background: Pubertal timing is closely linked to growth regulated by the growth hormone/insulin-like factor (GH/IGF) axis that includes IGF-regulating factors such as pregnancy-associated plasma protein-A/A2 (PAPP-A/PAPP-A2) and stanniocalcin 2 (STC2). We investigated the association between height, IGF-I concentration, and PAPPA, PAPPA2, and STC2 genotypes on the timing of female pubertal milestones., Methods: Height, IGF-I, and genotypes were analyzed in 1382 Danish girls from the general population, 67 patients with tall stature (height ≥2 SD), and 124 patients with short stature (height ≤-2 SD). The main outcomes were breast stage and menarche., Results: Thelarche occurred significantly earlier in patients with tall stature (mean age 9.37 years [95% confidence interval (CI) 8.87-9.87]) and later in patients with short stature (11.07 years [95% CI 10.7-11.43]) compared with girls within the normal range (9.96 years [95% CI 9.85-10.07]) (p = 0.02 and p < 0.01, respectively). Girls with higher IGF-I levels experienced thelarche and menarche earlier compared with the rest of the cohort (p < 0.01). Genotypes were not associated with age at thelarche nor menarche, but the PAPPA2 minor allele carriers were shorter compared with major allele carriers, p = 0.03., Conclusions: Height and IGF-I, but not PAPP-A, PAPP-A2, and STC2 genotypes, were negatively associated with age at thelarche and menarche., Impact: Girls with tall and short stature enter puberty earlier and later compared with girls with normal height. Girls with higher insulin-growth factor-I in childhood enter puberty earlier. Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood. Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing., (© 2021. International Pediatric Research Foundation, Inc.)

Aim: The aim was to assess the influence of dietary counselling on the pubertal development and hormonal status in healthy adolescents., Methods: We used a subcohort of 193 healthy boys (52%) and girls (48%) from the Special Turku Coronary Risk Factor Intervention Project. Participants were recruited by nurses at the well-baby clinics in Turku Finland in 1990-1992 and randomised into intervention and control groups. Intervention children received low-saturated fat and low-cholesterol dietary counselling initiated at seven months of age. Participants were examined once a year with Tanner staging, anthropometric measurements and serial reproductive hormones from 10 to 19 years of age. In girls, postmenarcheal hormones were not analysed., Results: Pubertal hormones in boys or girls did not differ between the intervention and control groups. However, we observed slight differences in pubertal progression by Tanner staging and in anthropometric parameters. The intervention boys progressed faster to G4 (p = 0.008), G5 (p = 0.008) and P5 (p = 0.03). The intervention boys were taller than control boys (p = 0.04), while weight and body mass index did not differ., Conclusion: Dietary intervention did not affect pubertal hormonal status. This finding supports the safety of implemented counselling in respect to puberty., (©2018 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events., Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively., Design: Cross-sectional and longitudinal study of healthy girls., Setting: Population-based study in the Copenhagen area., Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.-211G>T (rs10835638), FSHR c.-29G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921)., Main Outcome Measures: Clinical pubertal staging and anthropometric data., Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P < 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.-211G>T (rs10835638) and FSHR c.-29G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores)., Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls., (Copyright © 2017 Endocrine Society)

Context: Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing., Objective: To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys., Design: Cross-sectional and longitudinal study of two cohorts of healthy boys., Setting: This was a population-based study., Patients or Other Participants: Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039G>A., Main Outcome Measures: Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels., Results: Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95% confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (β = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance., Conclusion: In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing., (Copyright © 2017 by the Endocrine Society)

Context: Epidemiological evidence on maternal and paternal heritability of the wide normal variation within pubertal timing is sparse., Objective: We aimed to estimate the impact of parental pubertal timing on the onset of puberty in boys and girls., Design: Annual pubertal examinations of healthy children in a longitudinal cohort study. Information on parental timing of puberty (earlier, comparable to, or later compared to peers) and menarche age was retrieved from questionnaires., Participants: A total of 672 girls and 846 boys., Main Outcome Measures: Age at onset of pubic hair (PH2+), breasts (B2+), and menarche in girls; and PH2+, genital stage (G2+), and testis >3 mL with orchidometer (Tvol3+) in boys., Results: In boys, pubertal onset was significantly associated with pubertal timing of both parents. PH2+ and Tvol3+ were earlier: -11.8 months (95% confidence interval, -16.8, -6.8)/-8.9 (-12.8, -4.9), and -9.5 (-13.9, -5.1)/-7.1 (-10.4, -3.7) if the father/mother, respectively, had early pubertal development compared to late. In girls, menarche was significantly associated with both parents' pubertal timing: -10.5 months (-15.9, -5.1)/-10.1 (-14.3, -6.0) if father/mother had early pubertal development compared to late. For the onset of PH2+ and B2+ in girls, estimates were -7.0 months (-12.6, -1.4) and -4.1 (-10.6, +2.4)/-6.7 (-11.0, -2.5), and -6.7 (-11.0, -2.0) for fathers/mothers, respectively. Maternal age of menarche was significantly associated with the onset of all pubertal milestones except PH2+ in girls., Conclusions: Maternal as well as paternal pubertal timing was a strong determinant of age at pubertal onset in both girls and boys. Age at breast and pubic hair development in girls, which has declined most during recent years, seemed to be least dependent on heritability.

Background and Objectives: Studies of adolescents often use self-assessment of pubertal maturation, the reliability of which has shown conflicting results. We aimed to examine the reliability of child and parent assessments of healthy boys and girls., Methods: A total of 898 children (418 girls, 480 boys, age 7.4-14.9 years) and 1173 parents (550 daughters, 623 sons, age 5.6-14.7 years) assessed onset of puberty or development of breasts, genitals, and pubic hair according to Tanner stages by use of a questionnaire and drawings. Physicians' assessments were blinded and set as the gold standard. Percentage agreement, κ, and Kendall's correlation were used to analyze the agreement rates., Results: Breast stage was assessed correctly by 44.9% of the girls (κ = 0.28, r = 0.74, P < .001) and genital stage by 54.7% of the boys (κ = 0.33, r = 0.61, P < .001). For pubic hair stage 66.8% of girls (κ = 0.55, r = 0.80, P < .001) and 66.1% of boys (κ = 0.46, r = 0.70, P < .001) made correct assessments. Of the parents, 86.2% correctly assessed onset of puberty in girls (κ = 0.70, r = 0.71, P < .001) and 68.4% in boys (κ = 0.30, r = 0.37, P < .001). Children who underestimated were younger and children who overestimated older than their peers who made correct assessments. Girls and their parents tended to underestimate, whereas boys overestimated their pubertal stage., Conclusions: Pubertal assessment by the child or the parents is not a reliable measure of exact pubertal staging and should be augmented by a physical examination. However, for large epidemiologic studies self-assessment can be sufficiently accurate for a simple distinction between prepuberty and puberty., (Copyright © 2015 by the American Academy of Pediatrics.)

The influence of sex, age, pubertal development and oral contraceptives on dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17α-hydroxyprogesterone (17-OHP), Δ4-androstenedione (Adione), testosterone (T), calculated free testosterone (fT), free androgen index (FAI) and selected ratios in 1798 serum samples from healthy children, adolescents and young adults was evaluated. Samples were analyzed by Turboflow-LC-MS/MS. Sex hormone-binding globulin was analyzed by immunoassay. All steroid metabolite concentrations were positively associated with age and pubertal development in both sexes and generally higher in males than in females except for Adione. The pubertal rise in T in males was more pronounced compared to females, reflecting contribution from the testes. Ratios between steroid metabolites varied and depended on sex and age. All ratios were lower during infancy compared to later in life. Use of oral contraceptives significantly lowered serum concentrations of all steroid metabolites, fT, FAI, the 17-OHP/Adione, the Adione/T and the DHEA/Adione ratios, but not the DHEA/DHEAS ratio. We provide reference ranges for DHEA, DHEAS, 17-OHP, Adione, T, fT, FAI and selected ratios in relation to sex, age and pubertal development. Use of oral contraceptives strongly influences adrenal steroidogenesis and should be considered when diagnosing and monitoring treatment of patients with disorders of sex development., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression) entered puberty 7.4 (2.5-12.4) months later than carriers of the common variants FSHR -29GG+GA, p = 0.003. To our knowledge, this is the strongest genetic effect on age at pubertal onset in girls published to date.

We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989-1991, 1377 had antenatal serum stored without thawing at -80 °C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for anti-Müllerian hormone (AMH), inhibin B, sex hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. Four hundred microlitres of the frozen maternal serum underwent isotope-diluted liquid chromatography-tandem mass spectrometry, with preceding enzymatic deconjugation followed by solid-phase extraction to determine phthalate exposure. Two hundred and forty four girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 samples available. Several phthalates were negatively associated with maternal SHBG, and associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate was associated with a non-significant tendency towards an earlier age at menarche (P=0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate (P=0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Σall phth.m) were protective against PCOS in adolescence (P=0.001 and P=0.005 respectively). There were negative associations of MEP with PCO (P=0.022) and of MEP with serum AMH (P=0.031). Consequently, our data suggest that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.

Insulin-like factor 3 (INSL3) is a promising marker of Leydig cell function with potentially high clinical relevance. Limited data of INSL3 levels in relation to other reproductive hormones in healthy pubertal boys exist. In this study, we aimed to evaluate longitudinal serum changes in INSL3 compared with LH, FSH, testosterone, inhibin B, and anti-Müllerian hormone (AMH) during puberty in healthy boys. Ten boys were included from the longitudinal part of the COPENHAGEN Puberty Study. Pubertal evaluation, including testicular volume, was performed and blood samples were drawn every 6 months for 5 years. Serum concentrations of testosterone were determined by a newly developed LC-MS/MS method, and serum concentrations of INSL3, AMH, inhibin B, FSH, and LH respectively were determined by validated immunoassays. The results showed that serum INSL3 levels increased progressively with increasing age, pubertal onset, and testicular volume. In six of the ten boys, LH increased before the first observed increase in INSL3. In the remaining four boys, the increase in LH and INSL3 was observed at the same examination. The increases in serum concentrations of LH, testosterone, and INSL3 were not parallel or in ordered succession and varied interindividually. We demonstrated that INSL3 concentrations were tightly associated with pubertal onset and increasing testicular volume. However, the pubertal increases in LH, INSL3, and testosterone concentrations were not entirely parallel, suggesting that INSL3 and testosterone may be regulated differently. Thus, we speculate that INSL3 provides additional information on Leydig cell differentiation and function during puberty compared with traditional markers of testicular function.

Background: Longer androgen receptor gene CAG trinucleotide repeats, AR (CAG)n, have been associated with reduced sensitivity of the androgen receptor (AR) in vitro as well as in humans. Furthermore, short AR (CAG)n have been associated with premature adrenarche., Objective: The aim of the study was to evaluate associations between the AR (CAG)n polymorphism and development of pubic hair, levels of androgens, and body fat content in healthy boys., Methods: A longitudinal study of 78 healthy boys (age 6.2-12.4 years at inclusion) from the COPENHAGEN Puberty Study was conducted with clinical examinations and blood samples drawn every 6 months. The AR (CAG)n length was established by direct DNA sequencing and reproductive hormones were measured in serum by standardized analyses., Results: Median AR (CAG)n length was 22 (range, 17-30). Before puberty (at 10 years of age), boys with long CAG repeats (CAG ≥ 24) had lower levels of SHBG (88 vs 125 nmol/L) (P < .05) and a nonsignificant trend toward higher median skinfold thickness (41 vs 31 mm) (P = .06) compared with boys with an average number of CAG repeats (CAG 21-23). In contrast, the inverse association was observed at puberty (at 12 years of age) in boys with short CAG repeats (CAG 17-20) (P < .05). Serum levels of LH and testosterone (at 12 years) were significantly higher in boys with long CAG repeats compared with boys with an average number of CAG repeats (P = .05)., Conclusion: The observed associations between AR (CAG)n and peripubertal fat accumulation and serum SHBG concentrations indicate that this genetic polymorphism may influence the androgen-dependent fine-tuning of metabolic and reproductive factors at a young age.

Background: Pubertal onset is usually defined by breast development in girls and testicular growth in boys. Pubarche is defined as the attainment of pubic hair and is considered as a sign of pubertal transition. Pubarche is preceded by a gradual increase in production of adrenal androgens, DHEA and Δ4-androstenedione (Adione), a process termed adrenarche., Objective: To study the natural course of pubertal transition and the associations with adrenarche, body fat, and linear growth., Design and Methods: A longitudinal study of 179 healthy children (89 girls) with higher socioeconomic background examined every 6 months for 5 years. Pubic hair stage, breast stage, genital stage, testicular volume (TV), height, weight, and four skinfolds were measured., Results: In girls, median age (25th and 75th percentiles) at thelarche (B2+) was 10.1 years (9.3-10.9). In boys, median age at attaining a TV >3 ml was 11.5 years (10.9-12.0). Median age at pubarche (PH2+) was 10.9 years (10.3-11.4) in girls and 11.6 years (10.8-12.4) in boys. Only 6.8% (4/59) of the girls and 24.6% (15/61) of the boys developed pubic hair as the first isolated sign of puberty. Serum DHEAS and Adione increased with age, although the increase in Adione was most pronounced in girls. No associations between early age at thelarche/testicular growth and increased body fat (BMI and sum of four skinfolds) were observed., Conclusion: Danish children rarely experience pubarche as the first sign of puberty. No associations between age at pubertal onset and body composition were found. Circulating levels of Adione, but not DHEAS, increased with the onset of puberty, although with large interindividual variability.

Background: Ovarian function in Turner syndrome (TS) patients depends on the specific karyotype. This retrospective clinical study evaluates the pituitary-gonadal axis during infancy, childhood and adolescence in TS patients according to karyotype and ovarian function., Methods: A cohort of 70 TS patients (0-16 years) followed at a tertiary referral centre for paediatric endocrinology were included. Longitudinal measurements of reproductive hormones (FSH, LH, inhibin B and estradiol) prior to hormonal replacement treatment in 66 patients related to karyotype (A, 45,X; or B, miscellaneous karyotypes) and ovarian function (spontaneous puberty or absent spontaneous puberty) were compared with an age-matched reference range of 2406 healthy Danish females., Results: The prevalence of spontaneous puberty was 6% for 45,X and 54% for miscellaneous karyotypes, P = 0.001. In all TS patients, gonadotrophins were higher during infancy and at expected puberty compared with levels at mid-childhood, where 21/25 and 23/27 had FSH and LH levels, respectively, within the reference range. In patients with absent spontaneous puberty, 10/12 had FSH in the reference range during the mid-childhood nadir. 45,X-TS patients had undetectable inhibin B at 0-16 years. Ovarian failure was predicted in 20/20 patients with exclusively undetectable inhibin B, while 9/10 with detectable inhibin B entered puberty spontaneously. Estradiol levels were elevated from 4 to 8 years., Conclusions: Ovarian function in TS patients is associated with the specific karyotype, and multiple undetectable inhibin B values during mid-childhood may predict absence of spontaneous puberty, although the specificity of the test is low. The biphasic age pattern of gonadotrophins was preserved in all patients, and spontaneous gonadotrophins are not useful as a diagnostic marker for TS in girls aged 6-10 years.

Context and Objective: Few studies have focused on the interrelation between thyroid size, anthropometric variables, and IGF-I in adults, but such data are lacking for children. We have investigated thyroid gland volume and several hormonal and anthropometric variables in prepubertal children., Design and Participants: A total of 859 prepubertal euthyroid Danish children aged 4-9 yr underwent a thorough clinical investigation, including anthropometrical measurements and determination of TSH, thyroid hormones, autoantibodies, urinary iodine excretion, and thyroid volume (TV) by ultrasound. Longitudinal growth data from birth were available., Results: TV increased significantly with age (r = 0.487; P < 0.001). Mean TV +/- sd for different age groups were as follows: 4 yr, 2.2 +/- 1.4 ml; 5 yr, 2.5 +/- 1.3 ml; 6 yr, 2.8 +/- 1.3 ml; 7 yr, 3.2 +/- 1.3 ml; 8 yr, 3.5 +/- 1.3 ml; 9 yr, 3.7 +/- 1.3 ml. We found a significant positive association between IGF-I and TV (P < 0.001). Furthermore, in multiple regression analyses, TSH (P < 0.013), free T(4) (P < 0.001), lean body mass (P < 0.001), and body surface area (P < 0.001) as well as other anthropometrical measurements were identified as factors significantly associated with TV. Family history of thyroid disease and presence of incidental abnormal ultrasound findings were also positively associated with TV (P = 0.025 and 0.022, respectively)., Conclusions: In our cohort of prepubertal Danish children, the GH/IGF-I-axis was positively correlated with thyroid size, suggesting a role in the regulation of thyroid growth. Moreover, anthropometric measurements, in particular body surface area, were the best predictors of TV.

Context: Recent studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Clinical studies including a contemporary control group are lacking., Objective: The objective was to study clinical, biochemical, and ultrasonographic markers of pituitary-gonadal activation in prepubertal adopted girls and a control group in the same age categories., Setting: The study took place at University Hospital, Copenhagen, Denmark., Design and Participants: The study included randomly selected internationally adopted girls [(n = 99; mean age, 6.9 (5.1-8.5) yr] and controls of Danish origin [n = 93; mean age, 6.8 (5.2-8.5) yr] who were studied cross-sectionally., Methods: Height, weight, and pubertal stage were assessed with serum levels of reproductive hormones. Size and morphology of internal genitals were evaluated by ultrasonography. Bone age was evaluated by x-ray of the left hand., Results: Serum values of FSH were significantly higher in prepubertal adopted girls compared with controls [median, 1.4 (95% confidence interval, 0.4-3.6) vs. 1.0 (0.4-2.4) IU/liter; P <0.001]. Serum estradiol was above detection limit (>18 pmol/liter) in 46.5% of prepubertal adopted girls and 20.7% of controls (P = 0.001). In prepubertal adopted girls, the proportion of measurable samples increased significantly with age [odds ratio, 2.5 (95% confidence interval, 1.3-5.0; P = 0.009]. In controls, the odds ratio was 1.0 (0.6-1.7) (P = 0.9). Serum SHBG levels were significantly lower in prepubertal adopted girls compared with controls [99.0 (50.4-153.0) vs. 115.0 (53.1-202.1); P < 0.001]., Conclusion: Five- to 8-yr-old adopted girls showed signs of increased pituitary as well as gonadal activity despite prepubertal phenotype in the majority of girls. Our findings suggest that early onset of puberty in adopted girls is centrally driven.

Context Nonprogressive premature thelarche (PT) is a self-limiting variant of early puberty, while idiopathic central precocious puberty (ICPP) is a disorder that causes progressive development of secondary sexual characteristics and often requires treatment. The diagnostic differentiation between these conditions is important but can be challenging since they often both initially present clinically with isolated breast development. Objective To describe relevant clinical variables in a large cohort of girls referred for early puberty, and to evaluate clinical and biochemical parameters to distinguish between girls with ICPP and PT. Methods This retrospective study included 1361 girls referred with signs of early puberty to a single, tertiary center from 2009 to 2019. We evaluated clinical presentation, medical history, growth velocity, bone age, hormonal serum concentrations, and gonadotropin-releasing hormone (GnRH) test results. Results Central precocious puberty was diagnosed in 11% (ICPP: n = 143, organic CPP: n = 11) girls, whereas 8% (n = 91 girls) presented with PT. Receiver operating characteristic (ROC) analysis showed several biochemical and anthropometric markers as potential parameters to differentiate between ICPP and PT; however, none were individually adequate. Principal component analysis (PCA)–derived clinical and hormone profiles could predict girls with ICPP from girls with PT with a specificity of 90% and sensitivity of 84%, outperforming any single marker. Conclusion Differentiation of girls with ICPP and PT can be supported by individual clinical and biochemical parameters. However, dimension reduction of clinical and hormonal profiles by PCA improved the diagnostic value, which in the future may support the diagnostic process as a supplement to the GnRH test in evaluation of pubertal disorders. [ABSTRACT FROM AUTHOR]

Objective: We designed a longitudinal study to investigate the association between the ages of central pubertal activation and the appearance of clinical signs of puberty and determined total luteinizing hormone (LH) immunoreactivity in daytime‐ and nocturnal sleeptime‐excreted urine samples. Patients and Measurements: Thirty healthy volunteers (17 boys and 13 girls, aged 3.4–15.2 years and 4.3–14.3 years, respectively, at the beginning of the study) were included. Male and female subjects were followed for an average of 15 visits during 5.5 and 5.8 years on average, respectively. At each visit, subjects provided 24‐h urine samples divided into nocturnal sleeptime and waketime portions according to the participant's sleep‐and‐wake rhythm. Total urinary LH (U‐LH) concentrations were measured in duplicate by Delfia® IFMA (Wallac), which has been designed specifically to detect intact LH as well as the beta subunit and its core fragment, but not the human chorionic gonadotropin. Results: The initial increases in nocturnal sleeptime total U‐LH concentrations over the cutoff value of 0.7 IU/L occurred at around the same time (around 9–10 years of age) in both sexes, which could not be detected in waketime urine samples. The mean first age for the nocturnal sleeptime total U‐LH concentrations to reach or surpass the cutoff was 10.7 years (range: 10.2–11.6 years) in boys and 11.8 years (range: 10.7–13.4 years) in girls, showing no statistically significant difference between the sexes (p =.15). The mean time span from the age at which sleeptime total U‐LH concentration first exceeded the 0.7 IU/L level to observing pubertal stage 2 was 1.5 years in boys and 0.1 years in girls. Conclusions: Findings in our population with a limited sample size suggest that the timing of central pubertal activation is a sex‐independent phenomenon, which can be observed by monitoring the nocturnal sleeptime total LH concentrations in urine. The lag time from central pubertal activation of gonadotropin secretion to the clinical onset of puberty is significantly longer in boys. [ABSTRACT FROM AUTHOR]

Windkessel function is governed by conductance artery compliance that is associated with cardiovascular disease in adults independently of other risk factors. Sex-related differences in conductance artery compliance partly explain the sex-related differences in risk of cardiovascular disease. Studies on sex-related differences in conductance artery function in prepubertal children are few and inconclusive. This study determined the conductance artery compliance and cardiac function by magnetic resonance imaging in 150 healthy children (75 girls) aged 7-10 yr. Any sex-related difference in conductance artery function was determined with correction for other potential predictors in multivariable linear regression models. Our data showed that ascending [crude mean difference 1.11 95% confidence interval (CI) (0.22; 2.01)] and descending [crude mean difference 1.10 95% CI (0.09; 1.91)] aortic distensibility were higher in girls, but differences disappeared after adjustment for pubertal status and other identified potential predictors. Systolic and diastolic blood pressure, cardiac output, left ventricle (LV) systolic function, and total peripheral resistance did not differ between the sexes. In girls, heart rate was 7 beats/min higher, whereas pulse pressure (by 2 mmHg), LV end-diastolic volume index (by 7 mL), and stroke volume (by 5 mL) were lower. LV peak filling rate indexed to LV end-diastolic volume was 0.5 s-1 higher in girls. In conclusion, prepubertal girls and boys have equal conductance artery function. Thus, the well-known sex difference in adult conductance artery function seems to develop after the onset of puberty with girls initially increasing aortic distensibility. NEW & NOTEWORTHY Although it has been suggested that sex differences in conductance artery function may exist early in childhood, this study demonstrates that the well-known, sex-related difference in conductance artery stiffness (hence Windkessel function) in adulthood is not established before puberty. Thus, healthy prepubertal girls and boys have comparable conductance artery compliance. In contrast to previous studies, our study suggests that pubertal girls develop a more distensible aorta than prepubertal children. [ABSTRACT FROM AUTHOR]

Context Controversy exists regarding associations between early-life growth patterns and timing of puberty. Objective This work aims to investigate associations between birth anthropometry, early growth patterns, and onset/progression of pubertal milestones in boys and girls. Methods Among children examined at birth (1997-2003) and at age 36 months in a mother-child cohort, pubertal Tanner stages (B1-5, PH1-5, G1-5) and testicular volume were examined by trained physicians at 1 to 5 follow-up examinations during childhood and adolescence (672 girls and 846 boys, 2006-2013). With parametric survival models we analyzed associations between birth weight, changes in SD scores (SDS) from birth to 36 months (ΔSDS 0-36 > 0.67 SD defining catch-up growth), and age at pubertal onset/attainment of late pubertal stages/menarche. Results A 1-kg higher birth weight was associated with earlier onset of B2+ (thelarche): –3.9 months (CI, –6.7 to –1.1 months), G2+ (gonadarche): –2.7 months (–5.3 to –0.1 months), Tvol3+ (testis size > 3 mL): –2.8 months (CI, –4.9 to –0.7 months), but with later G4+ and PH4+ in boys, and a slower progression from B2 to menarche (5.3 months [CI, 1.2 to 9.4 months]) in girls. Catch-up growth was associated with earlier PH2+ (pubarche) in girls (–4.1 months [CI, –7.6 to –0.6 months]), earlier PH2+ in boys (–3.4 months [CI, –6.6 to –0.2 months]), faster progression from B2 to menarche in girls (–9.1 months [CI, 14.6 to 3.5 months]), and earlier G4+ and PH4+ in boys. Conclusion Associations between birthweight and infancy catch-up growth differed for gonadarche and pubarche, and for early and late pubertal markers, with similar patterns in both sexes. [ABSTRACT FROM AUTHOR]

Study Question: Do variants of the genes encoding follicle stimulating hormone (FSH) beta subunit (B) and FSH receptor (R) impact circulating reproductive hormone levels and ovarian follicle maturation in healthy peripubertal girls?Summary Answer: FSHB and FSHR genetic variants exert, alone or their combination, distinct effects on reproductive hormone levels as well as ovarian follicle maturation in healthy peripubertal girls.What Is Known Already: FSHB and FSHR genetic variants impact reproductive hormone levels as well as associated pathologies in women. While FSHR c. 2039A>G is known to alter gonadotrophin levels in women, FSHR c.-29G>A has not yet been shown to exert effect and there are conflicting results concerning FSHB c.-211G>T.Study Design, Size, Duration: This population-based study included 633 girls recruited as part of two cohorts, the COPENHAGEN Puberty Study (2006-2014, a cross-sectional and ongoing longitudinal study) and the Copenhagen Mother-Child Cohort (1997-2002, including transabdominal ultrasound (TAUS) of the ovaries in a subset of 91 peripubertal girls).Participants/materials, Setting, Methods: Clinical examinations, including pubertal breast stage (Tanner's classification B1-B5) were performed. Circulating levels of FSH, luteinizing hormone (LH), estradiol, anti-Mullerian hormone (AMH) and inhibin-B were assessed by immunoassays. In a subset of the girls (n = 91), ovarian volume and the number/size of antral follicles were assessed by TAUS. Genotypes were determined by competitive PCR.Main Results and the Role Of Chance: FSHR c.2039A>G minor alleles were positively associated with serum FSH (β = 0.08, P = 0.004), LH (β = 0.06, P = 0.012) and estradiol (β = 0.06, P = 0.017) (adjusted for Tanner stages). In a combined model, FSHR c.-29G>A and FSHR c.2039A>G alleles were positively associated with FSH levels in early-pubertal girls (B2 + B3, n = 327, r = 0.1, P = 0.02) and in young adolescents (B4 + B5, n = 149, r = 0.2, P = 0.01). Serum AMH and inhibin B levels were not significantly influenced by the single nucleotide polymorphisms (SNPs). Single SNPs were not associated with follicles counts, however, a cumulative minor allele count (FSHB c.-211 G>T and FSHR c.-29G>A) was negatively associated with the number of large follicles (≥5 mm) (n = 91, P = 0.04) (adjusted for Tanner stages).Limitations, Reasons For Caution: Since we studied girls and young adolescents during pubertal transition, our study may not be fully comparable with previous studies on FSHB and FSHR variants in adult women. The group of young adolescents (Tanner B4 + B5) reflects the endocrine situation in adult women best, however, the group is not large enough to contribute substantially to the conflicting results concerning the influence of FSHB c.-211G>T in adult women. Furthermore, we have no information about the exact day of the menstrual cycle in the subgroup of girls with menarche.Wider Implications Of the Findings: The sex-specific interaction of FSHB and FSHR genetic variants and physiological as well as pathological conditions is being increasingly elucidated. The variant triplet set might serve as diagnostic and pharmacogenetic marker. For the first time, we show an additional effect of FSHR c.-29G>A on serum FSH levels in healthy girls. Moreover, morphological data suggest impaired FSH-induced maturation of ovarian follicles in minor allele carriers of FSHB c.-211G>T and FSHR c.-29G>A. This may explain previous findings of delayed pubertal onset in these girls.Study Funding/competing Interests: Funding was provided by the Danish Agency for Science, Technology and Innovation (09-067180), Danish Ministry of the Environment, CeHoS (MST-621-00065), Capital Region of Denmark (December 2011), Ministry of Higher Education and Science (DFF-1331-00113) and EDMaRC (Danish Ministry of Health). A.S.B. was funded from December 2015 by ReproUnion (EU Interreg Öresund-Kattegat-Skagerrak). The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Background: Pubertal onset is usually defined by breast development in girls and testicular growth in boys. Pubarche is detined as the attainment of pubic hair and is considered as a sign of pubertal transition. Pubarehe is preceded by a gradual increase in production of adrenal androgens, DHEA and 4Δ-androstenedione (Adione), a process termed adrenarche. Objective: To study the natural course of pubertal transition and the associations with adrenarche. body fat, and linear growth. Design and methods: A longitudinal study of 1 79 healthy children (89 girls) with higher socioeconomic background examined every 6 months for 5 years. Pubic hair stage, breast stage, genital stage. testicular volume (TV), height. weight. and four slcinfolds were measured. Results: In girls, median age (2 5th and 75th percentiles) at thelarche (B2 +) was 10.1 years (9.3-10.9). In boys. median age at attaining a TV > 3 ml was 11.5 years (10.9-12.0). Median age at pubarche (PH2 +) was 10.9 years (10.3-11,4) in girls and 11,6 years (10.8-12.4) in boys. Only 6.8% (4/59) of the girls and 24.6% (15/61) of the boys developed pubic hair as the lirst isolated sign of puberty. Serum DHEAS and Adione increased with age, although the increase in Adione was most pronounced in girls. No associations between early age at thelarche/ testicular growth and increased body fat (BMI and sum of four skinfolds) were observed. Conclusion: Danish children rarely experience pubarche as the lirst sign of puberty. No associations between age at pubertal onset and body composition were found. Circulating levels of Adione, but not DHEAS, increased with the onset of puberty although with large interindividual variability. [ABSTRACT FROM AUTHOR]

Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed. Objective: To evaluate the outcome of brain MRI in girls referred with early signs of puberty in relation to age at presentation as well as clinical and biochemical parameters. Method: A single-center study of 229 consecutive girls with early or precocious puberty who had brain imaging performed. We evaluated medical history, clinical and biochemical factors, and four groups were defined based on the outcome of their MRI. Results: Thirteen out of 208 (6.3%) girls with precocious puberty, but no other sign of CNS symptoms, had a pathological brain MRI. Importantly, all 13 girls were above 6 years of age, and 6 girls were even 8-9 years old. Twenty girls (9.6%) had incidental findings on brain MRI. Furthermore, 21 girls had known CNS pathology at time of evaluation. Basal LH was significantly higher in girls with newly diagnosed CNS pathology compared to girls with a non-pathological MRI (p = 0.025); no cut of value was found as values overlapped. Conclusion: A high frequency of 6-8 year old girls with precocious puberty in our study had a pathological brain MRI, which could not be predicted from any clinical nor biochemical parameters. Thus, we believe that girls with precocious pubertal development of central origin before 8 years of age should continue to be examined by a brain MRI. [ABSTRACT FROM AUTHOR]

• A novel, specific, and sensitive isotope diluted LC-MS/MS method was developed for simultaneous quantitation of 16 steroid hormone metabolites. • Steroid metabolites in serum from healthy infants, children, adolescents, and adults aged 0.17 months to 77 years (n = 2458) were analysed. • Sex- and age specific reference intervals of 15 steroid metabolites were established. Reference intervals covering the whole life span for all the metabolites in the steroid hormone biosynthesis quantified by sensitive and robust analytical methods are sparse or not existing. To develop a state-of-the-art LC-MS/MS method for simultaneous quantification of multiple steroid metabolites and to establish detailed sex- and age-specific reference intervals for 16 steroid metabolites. An isotope diluted LC-MS/MS method was developed for simultaneous quantitation of 16 steroid hormones. Serum samples from cross-sectional cohorts of healthy infants, children, adolescents, and adults aged 0.17 months to 77 years (n = 2458) were analysed. With this novel, specific, and sensitive LC-MS/MS method, it was possible to quantify progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, and cortisone in ≥90 % of the samples, while estrone sulfate, aldosterone and dehydroepiandrosterone were quantified in 77 %, 75 % and 60 % of the samples, respectively. 21-deoxycortisol was only detectable in 2.5 % of samples from healthy subjects. Sex- and age-dependent fluctuations observed in minipuberty, puberty and adulthood including the menopausal transition were modelled. This enabled us to establish valid reference intervals from birth to late adult life for both males and females. Detailed sex- and age-specific reference intervals of multiple, simultaneously quantified steroid metabolites by a novel and specific LC-MS/MS method provides a valuable tool for clinical practice and for future research. [ABSTRACT FROM AUTHOR]

Abstract: Bisphenol A (BPA), triclosan (TCS), benzophenone-3 (BP-3), dichoro- and phenyl phenols are industrial chemicals present in numerous consumer products such as polycarbonate plastics, preservatives in personal care products, sun screens, pesticides and fungicides, respectively, and they are all suspected endocrine disrupters. In this study the urinary excretion of eight phenols in Danish children recruited from the general population were investigated. One 24h urine and two consecutive first morning samples were collected from each of 129 healthy Danish children and adolescents (6–21 years). The concentrations of urinary phenols were analyzed by a new on-line TurboFlow-liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. Most of the analyzed phenols were detectable in more than 80% of the 24h urine samples and the median concentration of BPA, TCS, BP-3, 2,4-dichorophenol and 2,5-dichorophenol (analyzed as ∑DCP), 2-phenylphenol and 4-phenylphenol were 1.37, 1.45, 1.41, 0.65, 0.36 and 0.53ng/mL, respectively. The ranges of the excreted TCS and BP-3 were wide; from below limit of detection to maximum levels of 955ng/mL and 162ng/mL, respectively, while the other phenols were excreted in a more narrow range with maximum levels below 25ng/mL. Concentrations in first morning urine were in general higher than in 24h urine and comprised 30–47% of the absolute amount excreted during 24h. The youngest children aged 6–10 years had a significantly higher urinary BPA concentration (ng/mL) and also a relatively higher daily BPA excretion (ng/kg bw/24h) than the older children and adolescents. The opposite pattern was observed for TCS, BP-3 and ∑DCP for which urinary levels increased significantly with age. No gender difference or associations to pubertal development were observed. In conclusion, our study showed that Danish children were exposed to multiple phenols simultaneously. Small children were relatively more exposed to BPA than older children, while higher exposures to TCS, BP-3 and ∑DCP were seen among adolescents. [Copyright &y& Elsevier]

Objective: To investigate whether genetic polymorphisms in the FSH pathway (FSHB-211 G→T and FSHR 2039 A→G) affect serum levels of FSH, antimüllerian hormone (AMH), and age at pubertal onset. FSH secretion and FSH signal transduction are enhanced in carriers of FSHB GG and FSHR AA, respectively. Furthermore, the combined genotype FSHB GG+FSHR AA is the most favorable for male gonadal function, but the effect of this genotype has never been evaluated in peripubertal females. AMH is a marker of ovarian function and is negatively correlated with FSH in prepubertal girls.Design: Secondary analyses of a prospective cohort study.Setting: General community.Patient(s): We examined 78 healthy girls twice yearly for 6 years; the median age at baseline was 9.3 years.Intervention(s): None.Main Outcome Measure(s): Hormone levels were measured by immunoassays, and DNA was isolated from blood and genotyped by restriction fragment length polymorphism of polymerase chain reaction-amplified regions.Result(s): Carriers of FSHB GG+FSHR AA had higher FSH before pubertal onset (median 2.2 vs. 1.5 IU/L) and lower AMH (13.8 vs. 19.4 pmol/L) compared with carriers of other genotypes. In crude analysis, girls with FSHB GG+FSHR AA entered puberty earlier, 9.7 vs. 10.6 years. However, the difference was no longer statistically significant after including interval-, right-, and left-censored data in a probit analysis.Conclusion(s): The combined effect of FSHB GG+FSHR AA may potentiate the FSH pathway, which increases serum levels of FSH and reduces AMH. Common variations in genes regulating follicle growth may affect AMH levels independently of the number of resting primordial follicles. [ABSTRACT FROM AUTHOR]

Objective To report normative data on uterine volume and endometrial thickness in girls, according to pubertal stages; to evaluate factors that affect uterine volume; and to compare transabdominal ultrasound (TAUS) and magnetic resonance imaging (MRI). Design Cross-sectional study of a nested cohort of girls participating in The Copenhagen Mother-Child Cohort. Setting General community. Patient(s) One hundred twenty-one healthy girls, aged 9.8–14.7 years. Intervention(s) None. Main Outcome Measure(s) Clinical examination, including pubertal breast stage (Tanner classification: B1–B5). Uterine volume: ellipsoid TAUS (n = 112) and 3-dimensional TAUS (n = 111); ellipsoid MRI (n = 61). Endometrial thickness: TAUS (n = 110) and MRI (n = 60). Result(s) Uterine volume and endometrial thickness were positively correlated with pubertal stages; e.g., ellipsoid TAUS: r = 0.753, and endometrium TAUS: 0.648. In multiple regression analyses, uterine volume was associated with the number of large follicles (TAUS >5 mm) (Beta 0.270); estradiol (E 2 ) (Beta 0.504); and height (Beta 0.341). Volumes from ellipsoid vs. 3-dimensional TAUS were strongly correlated ( r = 0.931), as were TAUS and MRI: ellipsoid volume ( r = 0.891) and endometrial thickness ( r = 0.540). Uterine volume was larger in TAUS compared with MRI; mean difference across the measured range: 7.7 (5.2–10.2) cm 3 . Agreement was best for small uteri. Conclusion(s) Uterine volume and endometrial thickness increased as puberty progressed. Circulating E 2 from large follicles was the main contributor to uterine and endometrial growth. The TAUS and MRI assessments of uterus and endometrium were strongly correlated. [ABSTRACT FROM AUTHOR]