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Context: Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed., Objective: To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche., Design: A prospective, longitudinal population-based study., Patients or Other Participants: Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms., Intervention(s): None., Main Outcome Measure(s): Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth., Results: Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche., Conclusion: TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms., (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.

Puberty marks numerous physiological processes which are initiated by central activation of the hypothalamic-pituitary-gonadal axis, followed by development of secondary sexual characteristics. To a large extent, pubertal timing is heritable, but current knowledge of genetic polymorphisms only explains few months in the large inter-individual variation in the timing of puberty. We have analysed longitudinal genome-wide changes in DNA methylation in peripheral blood samples (n = 102) obtained from 51 healthy children before and after pubertal onset. We show that changes in single methylation sites are tightly associated with physiological pubertal transition and altered reproductive hormone levels. These methylation sites cluster in and around genes enriched for biological functions related to pubertal development. Importantly, we identified that methylation of the genomic region containing the promoter of TRIP6 was co-ordinately regulated as a function of pubertal development. In accordance, immunohistochemistry identified TRIP6 in adult, but not pre-pubertal, testicular Leydig cells and circulating TRIP6 levels doubled during puberty. Using elastic net prediction models, methylation patterns predicted pubertal development more accurately than chronological age. We demonstrate for the first time that pubertal attainment of secondary sexual characteristics is mirrored by changes in DNA methylation patterns in peripheral blood. Thus, modulations of the epigenome seem involved in regulation of the individual pubertal timing.

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.

Objective: IGF1 plays an important role in growth and metabolism during puberty. IGF1 levels are increased in girls with central precocious puberty (CPP). However, the relationship with insulin before and during gonadal suppression is unknown. In addition, the influence of the exon 3-deleted GH receptor gene (GHRd3) on IGF1 levels was evaluated., Design: Nine hundred and eleven healthy and 23 early pubertal girls (15 with CPP) participated and were evaluated by dual-energy X-ray absorptiometry (DXA) scans, fasting and oral glucose-stimulated insulin levels, IGF1 levels, and GHR genotyping. Fifteen girls with early puberty (13 with CPP) were treated with GNRH agonists and reevaluated after 3 and 12 months., Results: IGF1 and insulin levels were higher in girls with CPP compared with healthy controls after adjustment for age, bone age, and breast development (all P≤0.02). IGF1 levels were only significantly positively correlated with insulin levels in girls with CPP at baseline (P≤0.03). During gonadal suppression, changes in IGF1 levels were inversely associated with changes in insulin levels (P=0.04). The GHRd3/d3 genotype was associated with significantly higher IGF1 levels (P=0.01) but not with earlier pubertal timing in healthy girls. The distribution of the GHRd3 genotypes among girls with CPP did not differ significantly from healthy girls (P=0.2)., Conclusion: The increased IGF1 and insulin levels in girls with CPP may be causally interrelated. In addition, the GHRd3 allele positively influences IGF1 levels in a copy number-response relationship but not pubertal timing in healthy girls.

Context: The GH/IGF-I axis influences gonadal development and function. Recently, a deletion of exon 3 in the GH receptor gene (GHRd3) has been linked to increased responsiveness to GH., Objective: Our objective was to evaluate the influence of the GHRd3 gene on birth size and pubertal onset., Design and Setting: We conducted a cross-sectional study, part of The COPENHAGEN Puberty Study, at a tertiary center for pediatric endocrinology., Participants: Participants included 618 healthy boys aged 6.1-19.8 yr., Main Outcome Measures: We assessed pubertal onset by genital staging and testicular palpation and parental reported birth weight and length. GHR genotypes were determined by multiplex PCR., Results: Age at onset of genital development (G2+) was significantly earlier in the GHRd3 homozygotes (GHRd3/d3) [10.86 (10.35-11.37) yr, mean (95% confidence interval)] compared with the full-length homozygotes (GHRfl/fl) [11.76 (11.35-12.00) yr, P = 0.002]. The odds ratio of having detectable testosterone levels for a given age was significantly higher in GHRd3/d3 compared with GHRfl/fl group (odds ratio = 3.1; 95% confidence interval = 1.2-8.9; P = 0.036). The GHRd3/d3 group the higher prepubertal IGF-I levels compared with the GHRfl/fl group (9.2% (0.1-18.1%), P = 0.048) after adjustment for IGF-binding protein-3 levels. Lower gestational-age-adjusted birth weight and length were found in the GHRd3/d3 group compared with the GHRfl/fl group and the GHRfl/d3 group, respectively (all P < or = 0.018)., Conclusion: The GHRd3/d3 genotype was associated with smaller birth size and earlier age at pubertal onset compared with the GHRfl/fl genotype. Thus, this common polymorphism could play a role for prenatal growth and gonadal development in boys.

Context: In the 1990s, the American population-based study NHANES III renewed the focus on possible secular trends in male puberty. However, no conclusions could be made on pubertal onset due to the lack of compatible data., Objective: The aim of the study was to evaluate secular trends in pubertal onset during the recent 15 yr and their relation to body mass index (BMI) in boys., Design and Setting: We conducted a cross-sectional study in 1991-1993 and a combined cross-sectional and longitudinal study in 2006-2008 (The Copenhagen Puberty Study) at a tertiary center for pediatric endocrinology., Participants: A total of 1528 boys aged 5.8 to 19.9 yr participated (n = 824 in 1991-1993, and n = 704 in 2006-2008). Genital and pubic hair stages as well as testicular volume by orchidometry were evaluated. Blood samples were analyzed for LH, FSH, testosterone, and SHBG., Main Outcome Measures: We measured age at onset of pubertal markers., Results: Onset of puberty, defined as age at attainment of testicular volume above 3 ml, occurred significantly earlier in 2006-2008 [11.66 yr (11.49-11.82); mean (95% confidence interval)] than in 1991-1993 [11.92 yr (11.76-12.08); P = 0.025]. Significantly higher LH, but not testosterone, levels were found in the 11- to 16-yr-old boys from 2006-2008 compared to 1991-1993 (P = 0.020). BMI Z-score increased significantly from 1991-1993 [0.044 (-0.016 to 0.104)] to 2006-2008 [0.290 (0.219-0.361); P < 0.001]. Interestingly, pubertal onset and LH levels were no longer significantly different between study periods after adjustment for BMI., Conclusions: Estimated mean age at onset of puberty has declined significantly during the recent 15 yr. This decline was associated with the coincident increase in BMI.

STUDY QUESTION Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? SUMMARY ANSWER Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. WHAT IS KNOWN ALREADY Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. STUDY DESIGN, SIZE, DURATION This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother–Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. MAIN RESULTS AND THE ROLE OF CHANCE In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. LIMITATIONS, REASONS FOR CAUTION Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. WIDER IMPLICATIONS OF THE FINDINGS Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. TRIAL REGISTRATION NUMBER N/A. [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]

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]