Pubertal Timing Research Articles

A Longitudinal Study of Pubertal Timing and Tempo on Body Shame Among Young Adolescent Girls and Boys

A Longitudinal Study of Pubertal Timing and Tempo on Body Shame Among Young Adolescent Girls and Boys

Associations between birth characteristics, pubertal timing and adult height.

This study investigated the association between gestational age and birth size with pubertal timing, measured as peak height velocity, and adult height. This retrospective, population-based study was conducted in Sweden in 2023. A sub-group of the 1974 and 1990 GrowUp Gothenburg cohorts was used (n = 4700, 50% males). The subgroup consisted of healthy individuals with Nordic ethnicity, known parental heights and measured adult heights. Data on birth characteristics (gestational age, birth length, birth weight) were collected. Pubertal timing was assessed as age at peak height velocity. Univariable linear regression analysis and bivariate correlations were conducted to answer the research questions. Gestational age was not associated with age at peak height velocity or adult height. Birth length and weight could explain 12% and 8% (p ≤ 0.001) respectively of attained adult height. However, birth length and birth weight could only explain the variation in age at peak height velocity to a small degree. This study showed that gestational age is not associated with age at peak height velocity or adult height. A positive relationship was found between birth size, particularly birth length, and adult height. No strong associations were found between birth size and age at peak height velocity.

7080 Copy Number Variation (CNV) in Self-Limited Delayed Puberty (SLDP)

Abstract Disclosure: Y. Al-Sayed: None. M. Ishida: None. C.L. Hall: None. S. Howard: None. SLDP is where the onset of puberty is more than 2-2.5 standard deviations later than the population mean age and is often familial with strong genetic determinants. The reproductive axis is regulated by gonadotropin-releasing hormone (GnRH), which plays a crucial role in initiating puberty and maintaining fertility through its pulsatile secretion. Disruption in GnRH neuron development or hypothalamic function can lead to DP. UK Biobank data has identified negative health outcomes associated with SLDP including early menopause/andropause and cognitive and psychosocial disabilities. Consequently, there has been extensive research to investigate genes affecting the hypothalamic-pituitary-gonadal (HPG) axis that might be implicated in the pathogenesis of DP by our group and others which has identified sequence variation contributing to the aetiology of SLDP. However, factors beyond nucleotide variations, such as epigenetic changes and CNVs can also lead to pubertal timing disorders. Moreover, CNVs are seen in multiple individuals (n=92) from the Deciphering Developmental Disorders study (https://www.deciphergenomics.org) with a phenotype including DP (HP:0000823). We performed whole genome sequencing on 49 probands with SLDP and subsequently, analysed the data for CNV. The data was initially called, annotated, filtered then partitioned for classification of CNVs using a command-line tool that implements the ACMG guidelines to evaluate the pathogenicity of germline duplications and deletions. Using an unbiased candidate gene approach, we identified several deletions that affected 60 known/predicted dosage sensitive genes and combines with functional enrichment analysis; This approach revealed potential molecular pathways and biological processes involved in the pathogenesis of SLDP, including histone acetylation, and neural plate development. To refine our findings, we applied additional filters, including known HPG axis genes, GWAS loci associated with pubertal timing, decipher CNV tracks, and DP gene panels, to narrow down large number of rare predicted damaging CNVs and prioritize those with potential relevance to DP. Our study highlights the potential role of CNVs in DP and expands our understanding of the molecular pathways and biological processes involved in this condition, shedding light on the complex mechanisms underlying DP. Presentation: 6/2/2024

7788 Importance of Neuronal STAT3, but Not ERK2 or mTOR, for Pubertal Timing and Reproductive Activity in Mice

Abstract Disclosure: R.A. Lord: None. M.A. Inglis: None. G.M. Anderson: None. The adipose-derived hormone leptin is important for regulating reproduction. The canonical JAK2/STAT3 pathway is the best-characterised leptin receptor signalling pathway. Neural STAT3 deletion is known to cause obesity; however, its reproductive influence is less understood. This experiment investigated whether STAT3 knockout from brain neurons or AgRP neurons, a neuronal population necessary for normal pubertal timing and reproduction, would unveil the necessity of STAT3 in reproductive function. We also tested the role of ERK2 and mTOR, two alternative leptin signalling molecules.Transgenic mice with a neuronal knockout were created via the Cre-loxP system. CamKinaseIIα-Cre mice were crossed with STAT3, mTOR or ERK2 floxed mice. AgRP-Cre mice were crossed with STAT3 floxed mice for STAT3 knockout in AgRP neurons. All groups were compared to Cre-negative littermate controls (n=6-12/group). Puberty onset was assessed post-weaning by examining genitalia development. Reproductive cyclicity and organ weights were measured in adults. Metabolic effects were evaluated through body weight, abdominal fat and fasting glucose measurements. Brain tissue analysis evaluated cellular responses to leptin for STAT3, ERK2, and mTOR. Data presented as mean ± SEM.Mice with ERK2 KO or mTOR KO showed no reproductive or metabolic deficits compared to controls. In marked contrast, neuronal STAT3 KO mice showed significantly increased body weight by 5 weeks of age and a 6-fold increase in abdominal adiposity as adults (both p<0.001 using two-way ANOVA and Student’s t-test respectively) compared to controls. Males had a significant 5-day delay in age at preputial separation (KO: 32.1±2.09 d; Control: 26.8±0.45 d, p<0.01, Student’s t-test) while females had a significant 7-day delay in vaginal opening (KO: 33.0±1.85 d, Control: 26.6±0.37 d, p<0.05, Student’s t-test), a 9-day delay in first estrus (KO: 37.8±1.89 d; Control: 29.4±0.65 d, p<0.01, Student’s t-test) and pronounced acyclicity. Neuronal STAT3 KO mice also had a >2-fold elevation in fasting glucose levels (p<0.001, Student’s t-test) and regressed reproductive organs. Female mice with STAT3 knockout in AgRP neurons showed significantly increased body weight (by 3 weeks [p<0.001], two-way ANOVA) and a significant 3-day delay in first estrus (KO: 31.1±0.71 d, Control: 28.6±0.45 d, p<0.01, Student’s t-test). These data show that neuronal STAT3 is critical for correctly timed puberty and subsequent fertility in male and female mice, whereas mTOR and ERK2 are not essential. These results have prompted a re-evaluation of previous conclusions about the role of STAT3 from experiments using LepR-Cre mice. Additionally, AgRP neuronal requirements for STAT3 exactly recapitulate AgRP requirements for leptin receptors. A better grasp of leptin signalling pathways will improve our understanding of how infertility arises due to metabolic disease. Presentation: 6/3/2024

9205 Copy Number Variation (CNV) in Self-Limited Delayed Puberty (SLDP)

Abstract Disclosure: Y. Al-Sayed: None. M. Ishida: None. C.L. Hall: None. S.R. Howard: None. SLDP is where the onset of puberty is more than 2-2.5 standard deviations later than the population mean age and is often familial with strong genetic determinants. The reproductive axis is regulated by gonadotropin-releasing hormone (GnRH), which plays a crucial role in initiating puberty and maintaining fertility through its pulsatile secretion. Disruption in GnRH neuron development or hypothalamic function can lead to DP. UK Biobank data has identified negative health outcomes associated with SLDP including early menopause/andropause and cognitive and psychosocial disabilities. Consequently, there has been extensive research to investigate genes affecting the hypothalamic-pituitary-gonadal (HPG) axis that might be implicated in the pathogenesis of DP by our group and others which has identified sequence variation contributing to the aetiology of SLDP. However, factors beyond nucleotide variations, such as epigenetic changes and CNVs can also lead to pubertal timing disorders. Moreover, CNVs are seen in multiple individuals (n=92) from the Deciphering Developmental Disorders study (https://www.deciphergenomics.org) with a phenotype including DP (HP:0000823). We performed whole genome sequencing on 49 probands with SLDP and subsequently, analysed the data for CNV. The data was initially called, annotated, filtered then partitioned for classification of CNVs using a command-line tool that implements the ACMG guidelines to evaluate the pathogenicity of germline duplications and deletions. Using an unbiased candidate gene approach, we identified several deletions that affected 60 known/predicted dosage sensitive genes and combines with functional enrichment analysis; This approach revealed potential molecular pathways and biological processes involved in the pathogenesis of SLDP, including histone acetylation, and neural plate development. To refine our findings, we applied additional filters, including known HPG axis genes, GWAS loci associated with pubertal timing, decipher CNV tracks, and DP gene panels, to narrow down large number of rare predicted damaging CNVs and prioritize those with potential relevance to DP. Our study highlights the potential role of CNVs in DP and expands our understanding of the molecular pathways and biological processes involved in this condition, shedding light on the complex mechanisms underlying DP. Presentation: 6/2/2024

12427 MKRN3 Methylation Abnormalities In Patients With Pubertal Disorders

Abstract Disclosure: N.C. Grosek: None. T. Silva: None. J.C. Magnotto: None. A. Latronico: None. A.P. Canton: None. Y. Chan: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Central Precocious Puberty (CPP) is caused by early reactivation of pulsatile GnRH secretion before age 8 years in girls and 9 years in boys. Delayed puberty (DP) is defined by the absence or incomplete development of sexual characteristics by age 13 years in girls and 14 years in boys. Environmental cues affect the HPG axis and timing of puberty via epigenetic mechanisms such as DNA methylation (DNAm). Inactivating mutations in the maternally imprinted Makorin Ring Finger 3 (MKRN3) gene are the most common genetic defect associated with CPP, representing ∼9% of patients with sporadic and familial CPP. Genomic imprinting occurs through differential methylation of CpG islands at a gene promoter or enhancer region. Differentially methylated regions (DMRs) regulate genetic imprinting. We hypothesized that transcription factor binding sites (TFBS) for ZFP57 (CpG57) andNRF1 (CpGs54+55) within the islet 3.7kb upstream of MKRN3 (MRKN3 islet) may impact expression. This study aimed to analyze if aberrant MKRN3 islet DNAm changes are associated with disorders of pubertal timing. Methods and Results: Germline DNA from 2 control patients was used to analyze the MKRN3 promoter region and islet DNAm profile. Bisulfite-treated DNA was amplified by PCR with primers targeting MKRN3 promoter and islet and submitted to Sanger sequencing. All CpG islands in the promoter region were 100% methylated, but those in the MKRN3 islet were differentially methylated with ∼50-60% methylated. DNA from our CPP cohort (n=71) underwent Next-Generation Sequencing analysis of bisulfite-treated DNA of these regions to identify the DMR potentially associated with MKRN3 imprinting. The MKRN3 islet covered CpG59-CpG49. Next, samples from our CPP cohort and patients with DP (n=44) and normal pubertal timing (n=33; 45% prepubertal, 55% pubertal) underwent pyrosequencing analyses of MKRN3islet. To compare DNAm levels between controls and our cohorts at each CpG island, T-tests were used: reported as mean±SEM. In the CPP cohort, 4/11 CpGs were significantly hypomethylated compared to controls (CpGs 54, 53, 51, 50). Specifically, the NRF1 TFBS was hypomethylated compared to controls (37.8 vs 41.6 ± 1.1, p<0.001) and DP (41.4 vs 43.8 ± 0.83, p=0.044). In the DP group, we found no significant difference in DNAm compared to controls. But they had hypermethylation of 4/11 CpGs compared to the CPP group, including the NRF1 TFBS (CpGs 55, 53, 51,50). Neither the CPP nor DP cohorts had significant DNAm differences at the ZFP57 TFBS compared to controls. Conclusion: Our study showed hypomethylation of 4 out of 11 CpGs in MKRN3 islet, including the NRF1 TFBS, in CPP compared to control and DP groups. On the other hand, NRF1 TFBS was hypermethylated in DPP compared to CPP. Further studies are needed to determine if these alternations in methylation are associated with MKRN3 expression levels and pubertal initiation. Presentation: 6/1/2024

7196 Variants in the Neurodevelopmental Gene BRINP2 are Associated with Severe Delayed Puberty

Abstract Disclosure: Y. Al-Sayed: None. R. Oleari: None. A. Cariboni: None. W. He: None. Y. Chan: None. S.R. Howard: None. Gonadotropin-releasing hormone (GnRH) is the master hormone regulating the reproductive axis and its pulsatile secretion is crucial for puberty onset and fertility. Disruption in GnRH neuron development or hypothalamic function can lead to absent or delayed puberty (DP) due to GnRH deficiency, with a phenotypic spectrum from severe delayed puberty to partial or complete Hypogonadotropic Hypogonadism (HH). HH can also be present as a shared trait with other neurodevelopmental disorders (NDDs). The aim of our study was to identify novel genetic etiology of severe DP by identifying variants in associated genes in our patient cohort; and ascertain the functional effects of identified variants of interest. Whole exome sequencing (WES) was performed on DNA samples from 180 probands with DP to identify potentially pathogenic rare coding variants in relevant gene pathways. Integrative analysis was performed on genomic data from human patients combined with transcriptomics analysis of rodent immortalized and primary GnRH neurons to determine novel regulators of GnRH neuronal development and function. Bone morphogenetic protein/retinoic acid inducible neural-specific 2 (BRINP2) was identified as a candidate gene of interest as it was found to be significantly upregulated during GnRH neuronal development in these single cell transcriptomics analyses. Mutations in this gene have been previously associated with NDDs such as autistic spectrum disorder (ASD). BRINP2 is localised to the olfactory bulb, a key site during GnRH neuron migration. Copy number variation in this gene is seen in multiple individuals from the Deciphering Developmental Disorders study with a phenotype including cryptorchidism and intellectual disability (https://www.deciphergenomics.org/gene/BRINP2/patient-overlap/cnvs). WES analysis identified four variants in BRINP2 (p.R726W, p.R649Q, p.I629V and p.D729N) in four unrelated probands with severely DP or partial HH, in combination with ASD or other NDD features. These four variants are all rare or ultra-rare and are predicted to be pathogenic by in silico tools including CADD, REVEL and SIFT. Protein expression of the four mutants was comparable to the reference protein. BRINP2 has been shown to inhibit neuronal cell proliferation by negative regulation of cell cycle transition and Brinp2 knockout mice show hyperactive behaviour representative of human attention-deficit hyperactivity disorder, but pubertal timing has not been assessed. Thus, BRINP2 is a novel candidate for GnRH deficiency with NDD and we have investigated the role of BRINP2 in GnRH biology via wildtype and mutant protein sub-cellular localization, as well as tissue expression in mouse hypothalamic tissue across development. Presentation: 6/2/2024

12672 MKRN3 Methylation Abnormalities In Patients With Pubertal Disorders

Abstract Disclosure: N.C. Grosek: None. T. Silva: None. J.C. Magnotto: None. A. Latronico: None. A.P. Canton: None. Y. Chan: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Central Precocious Puberty (CPP) is caused by early reactivation of pulsatile GnRH secretion before age 8 years in girls and 9 years in boys. Delayed puberty (DP) is defined by the absence or incomplete development of sexual characteristics by age 13 years in girls and 14 years in boys. Environmental cues affect the HPG axis and timing of puberty via epigenetic mechanisms such as DNA methylation (DNAm). Inactivating mutations in the maternally imprinted Makorin Ring Finger 3 (MKRN3) gene are the most common genetic defect associated with CPP, representing ∼9% of patients with sporadic and familial CPP. Genomic imprinting occurs through differential methylation of CpG islands at a gene promoter or enhancer region. Differentially methylated regions (DMRs) regulate genetic imprinting. We hypothesized that transcription factor binding sites (TFBS) for ZFP57 (CpG57) andNRF1 (CpGs54+55) within the islet 3.7kb upstream of MKRN3 (MRKN3 islet) may impact expression. This study aimed to analyze if aberrant MKRN3 islet DNAm changes are associated with disorders of pubertal timing. Methods and Results: Germline DNA from 2 control patients was used to analyze the MKRN3 promoter region and islet DNAm profile. Bisulfite-treated DNA was amplified by PCR with primers targeting MKRN3 promoter and islet and submitted to Sanger sequencing. All CpG islands in the promoter region were 100% methylated, but those in the MKRN3 islet were differentially methylated with ∼50-60% methylated. DNA from our CPP cohort (n=71) underwent Next-Generation Sequencing analysis of bisulfite-treated DNA of these regions to identify the DMR potentially associated with MKRN3 imprinting. The MKRN3 islet covered CpG59-CpG49. Next, samples from our CPP cohort and patients with DP (n=44) and normal pubertal timing (n=33; 45% prepubertal, 55% pubertal) underwent pyrosequencing analyses of MKRN3islet. To compare DNAm levels between controls and our cohorts at each CpG island, T-tests were used: reported as mean±SEM. In the CPP cohort, 4/11 CpGs were significantly hypomethylated compared to controls (CpGs 54, 53, 51, 50). Specifically, the NRF1 TFBS was hypomethylated compared to controls (37.8 vs 41.6 ± 1.1, p<0.001) and DP (41.4 vs 43.8 ± 0.83, p=0.044). In the DP group, we found no significant difference in DNAm compared to controls. But they had hypermethylation of 4/11 CpGs compared to the CPP group, including the NRF1 TFBS (CpGs 55, 53, 51,50). Neither the CPP nor DP cohorts had significant DNAm differences at the ZFP57 TFBS compared to controls. Conclusion: Our study showed hypomethylation of 4 out of 11 CpGs in MKRN3 islet, including the NRF1 TFBS, in CPP compared to control and DP groups. On the other hand, NRF1 TFBS was hypermethylated in DPP compared to CPP. Further studies are needed to determine if these alternations in methylation are associated with MKRN3 expression levels and pubertal initiation. Presentation: 6/1/2024

8428 Rare Variants in the MECP2 Gene in Two Boys with Central Precocious Puberty

Abstract Disclosure: A.P. Canton: None. J.B. Mebarak: None. M. Magnuson: None. S. Roberts: None. N. Mauras: None. M. Benson: None. S. Witchel: None. R.S. Carroll: None. A. Latronico: None. U.B. Kaiser: None. A. Abreu: None. Introduction: Central precocious puberty (CPP) occurs more frequently in girls and is usually labelled as idiopathic; however, in boys organic causes are more frequent. Identification of imprinted genes causing CPP have revealed epigenetic mechanisms underlying puberty. MECP2, an X-linked gene, encodes a methylated DNA reader protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder that may be associated with early pubertal development. Recently, rare variants in MECP2 have been recognized in girls with sporadic CPP with or without mild neurodevelopmental disorders. In our cohort of 78 patients with idiopathic CPP, no MECP2 mutations were identified in 73 girls. In this study, five boys with CPP were evaluated for potential MECP2 sequence variants. Methods and Results: Five boys with CPP were screened for MECP2 sequence variants using Sanger sequencing. At the time of CPP diagnosis, they had median (interquartile range) chronological age 9.2 yr (4.3), bone age advancement 2.1 yr (3.5), height SDS 2.3 (1.5), basal LH levels 1.6 IU/L (0.9), and testosterone levels 370 ng/dL (570). Organic causes of CPP were excluded. No MKRN3 or DLK1 mutations were identified. Familial segregation analysis was performed when appropriate. We identified a hemizygous MECP2 variant in a boy (Patient 1) who presented at age 2.7 yr with sporadic CPP. In addition, he had speech delay and behavioral changes, defined as autism spectrum disorder by neuropsychological assessment. He harbored an extremely rare (gnomAD AF=0.000004956) missense variant (p.Val312Ile) in exon 3 of MECP2, encoding the transcriptional repression domain, critical for protein function. The p.Val312Ile mutation was classified as likely pathogenic (ACMG criteria) with a potential association with the phenotype. Another hemizygous MECP2 variant was identified in a boy (Patient 2) who presented at age 8.0 yr with sporadic CPP; he had no neurodevelopmental conditions. He harbored a rare (gnomAD AF=0.00008) missense variant (p.Arg366Cys) in exon 3, encoding the C-terminal domain, classified as a variant of uncertain significance (ACMG criteria). Familial segregation analysis revealed that both boys inherited the MECP2 variants from their unaffected mothers, consistent with a pattern of clinical variability described in women with defects in X-linked genes.Conclusions: We identified rare MECP2 variants in two boys with sporadic CPP without classic features of Rett syndrome, expanding the phenotype of patients with MECP2 mutations, as described in girls. The MECP2 p.Val312Ile variant was likely pathogenic, whereas the functional significance of the p.Arg366Cys variant in still indeterminate. These findings provide additional evidence for a role of MECP2, an epigenetic factor, in the hypothalamic control of pubertal timing. Presentation: 6/1/2024

Examining Health Behaviors as Mechanisms Linking Earlier Pubertal Timing with Accelerated Epigenetic Aging in Late Adolescence.

Earlier pubertal timing is associated with accelerated epigenetic aging, but the underlying mechanisms are not well understood. This three-wave longitudinal study examined negative health behaviors, specifically substance use, short sleep duration, and poor diet quality in middle adolescence, as mediators of links between earlier phenotypic and perceived pubertal timing measured in early adolescence and epigenetic aging on three epigenetic clocks in late adolescence (GrimAge, DunedinPACE, and PhenoAge). Phenotypic pubertal timing measured physical pubertal maturation relative to chronological age, whereas perceived pubertal timing was based on adolescents' subjective interpretation of their pubertal timing relative to their peers. Participants included 1213 youth (51% female, 49% male; 62% Black, 34% White) who participated during early adolescence (mean age = 13.10 years), middle adolescence (mean age = 16.1 years) and late adolescence (mean age = 19.7 years). Results from a mediation model revealed a mediation effect of earlier phenotypic pubertal timing on accelerated GrimAge in late adolescence through higher substance use during middle adolescence. There was also a direct effect of earlier phenotypic pubertal timing on accelerated DunedinPACE in males. Sleep duration and diet quality did not emerge as mediators but shorter sleep duration predicted accelerated GrimAge in females. These findings suggest that higher substance use presents a mechanism through which earlier maturing youth experience faster epigenetic aging that puts them at risk for poorer health across the lifespan.

Impact of BMI on childhood growth, pubertal timing, and bone maturation: A comprehensive review and clinical implications

Introduction: Childhood obesity and undernutrition significantly affect growth patterns, pubertal timing, and bone maturation, leading to long-term health implications. Materials and Methods: A comprehensive literature review was conducted using databases such as PubMed, Google Scholar, and Scopus. Twenty-four studies, including a total of 40,732 patients, were analyzed from two tables examining the impact of BMI, growth patterns, pubertal timing, and bone maturation. Results: Children with high BMI exhibit accelerated linear growth during early childhood, that may be driven by elevated leptin levels, which stimulate growth before puberty. Despite early growth advantages, these children experience reduced height gain during adolescence due to advanced bone maturation and earlier closure of growth plates. High BMI is strongly linked to early puberty, especially in girls, as increased adipose tissue raises leptin levels, triggering early pubertal onset. Boys, however, show variability in pubertal timing, with severe obesity sometimes delaying puberty. In contrast, children with low BMI or undernutrition demonstrate delayed linear growth and delayed puberty. Nutritional deficits lead to reduced growth velocity, delayed pubertal onset, and extended pubertal periods due to a lack of adipose tissue and hormonal deficiencies in leptin and kisspeptin. Nutritional rehabilitation promotes catch-up growth, allowing for extended growth potential by delaying growth plate closure. However, full recovery may not occur in cases of prolonged or severe undernutrition. Advanced bone age in high BMI children shortens the pubertal growth spurt, while delayed bone maturation in undernourished children offers a prolonged period for potential growth, contingent on timely nutritional support. Conclusion: Timely interventions for childhood obesity and undernutrition are critical to improving growth outcomes and preventing long-term developmental delays. Early identification, nutritional rehabilitation, and lifestyle modifications can help optimize growth and pubertal development by addressing both advanced and delayed growth trajectories.

Lack of a genetic risk continuum between pubertal timing in the general population and idiopathic hypogonadotropic hypogonadism.

Pubertal timing is a highly heritable trait in the general population. Recently, a large-scale exome-wide association study has implicated rare variants in six genes (KDM4C, MC3R, MKRN3, PDE10A, TACR3, and ZNF483) as genetic determinants of pubertal timing within the general population. Two of the genes (TACR3, MKRN3) are already implicated in extreme disorders of pubertal timing. This observation suggests that there may be a pervasive "genetic risk continuum" wherein genes that govern pubertal timing in the general population, by extension, may also be causal for rare Mendelian disorders of pubertal timing. Hence, we hypothesized that the four novel genes linked to pubertal timing in the population will also contribute to idiopathic hypogonadotropic hypogonadism (IHH), a genetic disorder characterized by absent puberty. Exome sequencing data from 1322 unrelated IHH probands were reviewed for rare sequence variants (RSVs) (minor allele frequency bins: <1%; <0.1%; <0.01%) in the six genes linked to puberty in the general population. A gene-based rare variant association testing (RVAT) was performed between the IHH cohort and a reference public genomic sequences repository-the Genome Aggregation Database (gnomAD). As expected, RVAT analysis showed that RSVs in TACR3, a known IHH gene, were significantly enriched in the IHH cohort compared to gnomAD cohort across all three MAF bins. However, RVAT analysis of the remaining five genes failed to show any RSV enrichment in the IHH cohort across all MAF bins. Our findings argue strongly against a pervasive genetic risk continuum between pubertal timing in the general population and extreme pubertal phenotypes. The biologic basis of such distinct genetic architectures' merits further evaluation.

Pubertal timing in adolescence and adulthood: Relations among contemporaneous and retrospective measures.

Pubertal development has short- and long-term effects on psychological adjustment. Many studies of long-term effects rely on retrospective measurement of pubertal timing, but such measures often reflect different aspects of puberty than those assessed in adolescence, raising questions about the utility and interpretation of retrospective reports. The present study leveraged longitudinal data collected in adolescence and established adulthood to determine: (1) the correspondence between pubertal timing indexed from logistic growth curves of self-reported physical development assessed contemporaneously across adolescence and pubertal timing indexed relative to peers assessed retrospectively in adulthood; (2) the associations between the two pubertal timing measures and psychological adjustment; and (3) potential recall biases. Participants were 748 individuals (50.1% female; 91.6% White) from two longitudinal studies who reported on their pubertal development annually from Grades 3-9, psychological adjustment (age at sexual initiation, substance use, depression) in late adolescence, and retrospective pubertal timing in established adulthood (Mage = 32.76; SD = 4.43). Results indicate moderate-to-high convergence between retrospective and contemporaneous indices. Most participants, especially women, had the same pubertal timing classification (i.e., early, on time, or late), but early-maturing adolescents often recalled on-time development as adults. Retrospective and contemporaneous indices were associated with psychological adjustment in similar ways, with some attenuation in the retrospective measure, especially for men. There was little evidence of recall bias due to age at retrospective assessment or time since puberty. Findings generally support the use of retrospective pubertal timing measures, with the recognition that some relations with adjustment may be weakened. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Delinquency During Puberty as a Biosocial Behavior: Time-Varying Effects of Social Contexts on Girls’ Delinquency in South Korea

Using Time-Varying Effect Model (TVEM) to analyze five waves of nationally representative South Korean panel data, from Grades 8 to 12, this study investigates how the effects of delinquent peers, parental care, and compliance with school rules on delinquency likelihood change across adolescence for girls with early versus late pubertal timing. The results reveal complex nonlinear trajectories that differ by puberty group: delinquent peer influence becomes more pronounced for late maturers after Grade 10, parental care consistently suppresses delinquency only for early maturers, and school rule compliance relates negatively to delinquency in late maturers but positively in early maturers. The findings challenge the partial application of the maturity gap hypothesis to early maturers only, highlighting how both early and late maturers experience strain from off-time development but negotiate it differently through shifting interactions with key social contexts over adolescence.

Exposure to Per- and Polyfluoroalkyl Substances and Timing of Puberty in Norwegian Boys: Data from the Bergen Growth Study 2.

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants with endocrine-disruptive properties. Their impact on puberty in boys is unclear. In this cross-sectional study, we investigated the association between PFAS exposure and pubertal timing in 300 Norwegian boys (9-16 years), enrolled in the Bergen Growth Study 2 during 2016. We measured 19 PFAS in serum samples and used objective pubertal markers, including ultrasound-measured testicular volume (USTV), Tanner staging of pubic hair development, and serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone. In addition to logistic regression of single pollutants and the sum of PFAS, Bayesian and elastic net regression were used to estimate the contribution of the individual PFAS. Higher levels of the sum of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) were associated with later pubertal onset according to USTV (age-adjusted odds ratio (AOR): 2.20, 95% confidence interval (CI): 1.29, 3.93) and testosterone level (AOR: 2.35, 95% CI: 1.34, 4.36). Bayesian modeling showed that higher levels of PFNA and PFHxS were associated with later pubertal onset by USTV, while higher levels of PFNA and perfluoroundecanoic acid (PFUnDA) were associated with later pubertal onset by testosterone level. Our findings indicate that certain PFAS were associated with delay in male pubertal onset.

Predictors of Anterior Cruciate Ligament Tears in Adolescents and Young Adults

Background: Anterior cruciate ligament (ACL) injury in youth can lead to expensive treatment, lengthy rehabilitation, and long-term impairment. Injuries to the ACL are more common in adolescents who participate in organized sports. Purpose: To examine whether there is an association between age, physical activity patterns, pubertal timing (Tanner stage), or body mass index (obesity/overweight status) and the risk of developing an ACL injury in youth. Study Design: Cohort study; Level of evidence, 2. Methods: Data from the Growing Up Today Study (GUTS), a prospective cohort study of youth throughout the United States, were used in this study. From 1996 to 2003, questionnaires were sent to GUTS participants every 12 to 18 months to assess a variety of self-reported factors; in a related 2004 questionnaire, ACL tears and other diagnoses among the participants were reported. Cox proportional hazard models were run to determine the sex-specific association of activity patterns and pubertal timing with risk of developing an ACL tear. Results: A total of 4519 boys and 5622 girls (age: 9-15 years) were included, with 2.4% and 2.0% sustaining an ACL injury, respectively. Age was found to be a significant risk factor for ACL injury in both sexes (male: hazard ratio [HR] = 1.30 [95% CI, 1.14-1.48]; female: HR = 1.23 [95% CI, 1.10-1.38]). Mean hours per week engaged in vigorous activity was also predictive of a higher risk of ACL injury (male: HR = 1.04 [95% CI, 1.01-1.08]; female: HR = 1.10 [95% CI, 1.07-1.14]). The sports that were the most predictive of injury were running, basketball, soccer, and cheerleading/gymnastics in girls and running, football, and karate/martial arts in boys. Additionally, in boys, overweight/obese status was found to be a significant predictor of ACL injury (HR = 2.61 [95% CI, 1.60-4.26]). Furthermore, among 9- to 13-year-old girls, advanced Tanner stage was a strong predictor of injury risk (HR = 2.43 [95% CI, 1.10-5.36]). Conclusion: Age, time engaged in vigorous activity, overweight/obese status, and advanced Tanner stage were associated with an increased risk of ACL injury in young adults and adolescents. Further research with follow-up data will help complement this study and continue to highlight the risk factors associated with ACL reconstruction in adolescents and young adults.

Supplemental Material for Pubertal Timing in Adolescence and Adulthood: Relations Among Contemporaneous and Retrospective Measures

Supplemental Material for Pubertal Timing in Adolescence and Adulthood: Relations Among Contemporaneous and Retrospective Measures

Evaluating Phthalates and Bisphenol in Foods: Risks for Precocious Puberty and Early-Onset Obesity.

Recent scientific results indicate that diet is the primary source of exposure to endocrine-disrupting chemicals (EDCs) due to their use in food processing, pesticides, fertilizers, and migration from packaging to food, particularly in plastic or canned foods. Although EDCs are not listed on nutrition labels, their migration from packaging to food could inadvertently lead to food contamination, affecting individuals by inhalation, ingestion, and direct contact. The aim of our narrative review is to investigate the role of phthalates and bisphenol A (BPA) in foods, assessing their risks for precocious puberty (PP) and early-onset obesity, which are two clinical entities that are often associated and that share common pathogenetic mechanisms. The diverse outcomes observed across different studies highlight the complexity of phthalates and BPA effects on the human body, both in terms of early puberty, particularly in girls, and obesity with its metabolic disruptions. Moreover, obesity, which is independently linked to early puberty, might confound the relationship between exposure to these EDCs and pubertal timing. Given the potential public health implications, it is crucial to adopt a precautionary approach, minimizing exposure to these EDCs, especially in vulnerable populations such as children.

Pubertal Development and Pregnancy Outcomes Among System-Involved Youth

ABSTRACT System-involved youth are a vulnerable population at high-risk of experiencing numerous sexual reproductive health (SRH) outcomes. They are likely to have several risk factors for teen pregnancy and parenting including abuse and neglect histories, lack of a supportive consistent adult in their lives, and limited opportunities to experience normal romantic relationships. Issues of pubertal development are rarely addressed in this population. Data is from system-involved adolescents (n = 301) enrolled in a SRH intervention. The final analysis is restricted to those who were sexually active at baseline (n = 229). Most participants were African Americans between 13–21 years of age. More than 70% reported an early mean age of first sex. Approximately a quarter self-reported early pubertal development. Logistic regression was utilized to examine the odds of pregnancy in relation to self-reported pubertal timing. The findings support the need to develop programming for system-involved youth which address their unique needs.

Evaluation and comparison of nine growth and development-based measures of pubertal timing

BackgroundPubertal timing is heritable, varies between individuals, and has implications for life-course health. There are many different indicators of pubertal timing, and how they relate to each other is unclear. Our aim was to quantitatively compare nine indicators of pubertal timing.MethodsWe used data from questionnaires and height, weight, and bone measurements from ages 7–17 y in a population-based cohort of 4267 females and 4251 males to compare nine growth and development-based indicators of pubertal timing. We summarise age of each indicator, their phenotypic and genetic correlations, and how they relate to established genetic risk score (GRS) for puberty timing, and phenotypic childhood body composition measures.ResultsWe show that pubic hair in males (mean: 12.6 y) and breasts in females (11.5 y) are early indicators of puberty, and voice breaking (14.2 y) and menarche (12.7 y) are late indicators however, there is substantial variation between individuals in pubertal age. All indicators show evidence of positive phenotypic intercorrelations (e.g., r = 0.49: male genitalia and pubic hair ages), and positive genetic intercorrelations. An age at menarche GRS positively associates with all other pubertal age indicators (e.g., difference in female age at peak height velocity per SD higher GRS: 0.24 y, 95%CI: 0.21 to 0.26), as does an age at voice breaking GRS (e.g., difference in age at male axillary hair: 0.11 y, 0.07 to 0.15). Higher childhood fat mass and lean mass associated with earlier puberty timing.ConclusionsOur findings provide insights into the measurements of the timing of pubertal growth and development and illustrate value of various pubertal timing indicators in life-course research.