Timing Of Puberty Research Articles

ALKBH5 Reduces BMP15 mRNA Stability and Regulates Bovine Puberty Initiation Through an m6A-Dependent Pathway

The timing of puberty significantly influences subsequent reproductive performance in cattle. N6-methyladenosine (m6A) is a key epigenetic modification involved in the regulation of pubertal onset. However, limited research has investigated alterations in m6A methylation within the hypothalamic–pituitary–ovarian (HPO) axis during the onset of puberty. In this study, combined analysis of methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-seq) is used to describe the overall modification pattern of m6A in the HPO axis, while GSEA, KEGG, and GO analyses are used to describe the enrichment pathways of differentially expressed genes and differentially methylated genes. The m6A modifications of the differential genes KL, IGSF10, PAPPA2, and BMP15 and the pathways of cell adhesion molecules (CAMs), TGF-β, cell cycle, and steroid hormone synthesis may play roles in regulating the function of the HPO axis tissue during pubertal transition. Notably, BMP15′s m6A modification depends on the action of the demethylase ALKBH5, which is recognized by the reader protein YTHDF2, promoting bovine granulosa cell proliferation, steroid production, and estrogen secretion. This study reveals for the first time the modification mechanism of BMP15 m6A during the initiation of bovine puberty, which will provide useful information for improving the reproductive efficiency of Chinese beef cattle.

Disorders of puberty and neurodevelopment: A shared etiology?

The neuroendocrine control of puberty and reproduction is fascinatingly complex, with up- and down-regulation of key reproductive hormones during fetal, infantile, and later childhood periods that determine the correct function of the hypothalamic-pituitary-gonadal axis and the timing of puberty. Neuronal development is a vital element of these processes, and multiple conditions of disordered puberty and reproduction have their etiology in abnormal neuronal migration or function. Although there are numerous documented cases across multiple conditions wherein patients have both neurodevelopmental disorders and pubertal abnormalities, this has mostly been described ad hoc and the associations are not clearly documented. In this review, we aim to describe the overlap between these two groups of conditions and to increase awareness to ensure that puberty and reproductive function are carefully monitored in patients with neurodevelopmental conditions, and vice versa. Moreover, this commonality can be explored for clues about the disease mechanisms in these patient groups and provide new avenues for therapeutic interventions for affected individuals.

Lifelong impacts of puberty timing on human plasma metabolic profiles: A metabolome-wide Mendelian randomization study.

The aim was to investigate the causal relationship between puberty timing and plasma metabolites, accounting for birth weight, childhood and adulthood adiposity. The meta-analysis of genome-wide association studies (GWAS) for puberty timing was extracted from the ReproGen Consortium, involving 329 345 women of European ancestry. Summary data for 174 plasma metabolites were retrieved from a recently conducted cross-platform GWAS that involved a meta-analysis of three cohort studies (i.e. the Fenland, European Prospective Investigation into Cancer-Norfolk and INTERVAL studies) and three publicly available studies and included up to 86 507 participants. We conducted a two-sample Mendelian randomization (MR) analysis to infer the causal relationship of puberty timing on 174 plasma metabolites, complemented by a two-step and multivariable Mendelian randomization (MVMR) analysis to assess direct and indirect effects. Additionally, summary-level data from the UK Biobank were used for our replication analysis. The results of the two-sample MR provide moderate evidence supporting a causal relationship between puberty timing and 23 of 174 plasma metabolites (i.e. 7 acylcarnitines, 8 amino acids, 2 biogenic amines and 6 lysophosphatidylcholines). Even after single-nucleotide polymorphisms associated with birth weight and childhood adiposity were excluded, causal effects persisted for 16 metabolites (i.e. 8 acylcarnitines, 4 amino acids, 2 biogenic amines and 2 lysophosphatidylcholines). The two-step MR analysis provided evidence that the relationship between puberty timing and plasma metabolites was mediated by adulthood adiposity. Additionally, moderate evidence emerged for an independent causal effect of puberty timing on 10 metabolites through an MVMR analysis (i.e. 5 acylcarnitines, 2 amino acids, 1 biogenic amine, 1 lysophosphatidylcholine and 1 phosphatidylcholine). Furthermore, the replication analysis suggested the robustness of our results. In summary, our study provides compelling evidence that puberty timing has a causal influence on certain plasma metabolites, although this influence is largely mediated by adulthood adiposity.

Selective depletion of kisspeptin neurons in the hypothalamic arcuate nucleus in early juvenile life reduces pubertal LH secretion and delays puberty onset in mice.

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin-releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDyABL) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDyABL mice demonstrated normal invivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol-induced LH surges in KNDyABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes.

8134 Hypothalamic Dlk1 Expression is Not Essential for Preventing Early Maturation of the Reproductive Axis in Female and Male Mice

Abstract Disclosure: D.B. Macedo: None. H. Kim Kyeol: None. A. Abreu: None. A. Latronico: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Inactivating mutations in Delta-like homolog 1 (DLK1), a maternally imprinted gene on chromosome 14, have been recognized as a genetic cause of central precocious puberty (CPP) in humans. It is well established that the timing of puberty, especially in females, is highly sensitive to energy stores and metabolic cues, with lower body fat negatively correlated with age at puberty and menarche. Mice lacking Dlk1 have pre- and postnatal growth retardation. Despite their considerably lower body weight (BW), we found that Dlk1 deficient females achieved puberty at the same age as controls (‘relative precocious puberty’). Moreover, Dlk1 deficiency led to activation of the reproductive axis despite lower levels of kisspeptin and leptin, an adipose tissue hormone with a permissive/stimulatory effect on metabolic control of reproduction. Dlk1 is a transmembrane protein that plays an essential role in inhibiting adipocyte differentiation and its biologically active form is soluble. Increased hypothalamic expression postnatally suggests a neuroendocrine function, but the precise mechanism by which DLK1 deficiency leads to CPP is yet to be deciphered. In this study, we aimed to investigate the role of hypothalamic Dlk1 expression on pubertal onset without the interference of diminished BW, using a conditional knockout (cKO) mouse model. Methods and Results: We generated a targeted Dlk1 knockout mouse model by crossing mice expressing Cre recombinase under the control of Nestin gene (Nes Cre), expressed primarily in neuro-epithelial cells, with mice harboring the Dlk1 gene flanked by loxP sites (Dlk1fl). Since Dlk1 is imprinted and expressed only by the paternal allele, we bred heterozygous Dlk1fl/+ male mice with Nes Cre females to obtain Dlk1fl/Cre (Dlk1 cKO), Dlk1+/Cre (Nes Cre) and Dlk1+/+ (wild type - WT). We confirmed by RT-qPCR that Dlk1 mRNA was undetectable in the mediobasal hypothalamus of Dlk1 cKO adult male mice, whereas it was present in Nes Cre and WT mice. We noted a lower BW in Nes Cre compared to WT mice, as previously reported. However, no difference in BW was observed between Dlk1 cKO and Nes Cre mice at the timing of puberty (females: Dlk1 cKO 12.6 ± 0.8 g vs. Nes Cre 13.8 ± 0.2 g, P = 0.18; males: Dlk1 cKO 12.4 ± 0.2 g vs. Nes Cre 13.1 ± 0.5 g, P = 0.26). Puberty onset, assessed by age at vaginal opening (females) and at preputial separation (males), was not affected by hypothalamic Dlk1 deletion (Dlk1 cKO: 35.6 ± 2.7 days vs. Nes Cre 34.6 ± 0.7 days, P = 0.73; Dlk1 cKO 29.0 ± 0.6 vs. Nes Cre: 30.3 ± 0.6 days, P = 0.19). Conclusion: In contrast to global Dlk1 deficiency, targeted deletion of Dlk1 from neuronal and glial cells did not affect body weight or timing of pubertal onset. These findings suggest that Dlk1 originates from peripheral tissues, such as adipocytes, to regulate reproduction and metabolism. Presentation: 6/1/2024

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

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

12513 Prenatal Traffic Exposures Are Associated With Earlier Age At Menarche

Abstract Disclosure: E.L. Silva: None. Z. Wang: None. S. Rifas-Shiman: None. A. Fleisch: None. H. Gibson: None. D. Gold: None. J. Chavarro: None. M. Hivert: None. E. Oken: None. B. Coull: None. J.E. Hart: None. T. James-Todd: None. S. Mahalingaiah: None. Background: The trend towards younger age at menarche over several decades has raised concern as earlier menarche is associated with various adverse health outcomes throughout adulthood including higher risk of early menopause, reproductive cancers, and metabolic disease. Some have suggested environmental exposures early in life may contribute to the temporal trend. Here we aimed to determine the extent to which prenatal residential measures of fine particulate matter (PM2.5), black carbon (BC), and other markers for traffic-related air pollution are associated with earlier age at menarche. Study Methods: Our study population included all female offspring in Project Viva, a pre-birth prospective cohort, with available age at menarche data. We used daily spatiotemporal models to estimate prenatal residential PM2.5 and BC exposures overall and by trimester. Residential proximity to major roadway and traffic density within a 100m buffer were measured at birth. Age at menarche was assessed via questionnaires during pre-teen and teen years. We used Cox proportional hazards modeling, adjusted for sociodemographic variables and census tract median household income, to estimate hazard ratios (HRs) for the association between air pollutants and age at menarche (months), where HR>1 indicates earlier onset of age at menarche associated with increased exposure to air pollutants. We weighted observations by the inverse probability of having available outcome data among all female offspring to account for cohort attrition. Results: The study included 638 females born between 2000 and 2003. Mean (standard deviation (SD)) age at menarche was 12.7 (1.4) years. Mean (SD) prenatal PM2.5 and BC exposures were 11.3 (1.5) g/m3 and 0.72 (0.21) g/m3, respectively. Only 7% of the cohort lived within 100m of a major roadway at birth. Prenatal PM2.5 exposure was not associated with age at menarche and the exposure distribution was mostly below US standards at the time (range: 6.8-15.8 g/m3, interquartile range (IQR): 2.0-3.0 g/m3). Higher overall prenatal and 3rd trimester BC were associated with earlier age at menarche [e.g., HR: 1.26 (95% CI, 1.04, 1.54) per IQR increment in 3rd trimester BC]. Living within 100m of a major roadway (versus 200m) [HR = 1.42 (95% CI, 1.08, 1.86)] and living in areas in the 2nd or 3rd (versus 1st) tertile of traffic density [2nd tertile: HR = 1.37 (95% CI, 1.07, 1.76); 3rd tertile: HR = 1.30 (95% CI, 1.02, 1.66)] at birth were also associated with earlier age at menarche. Conclusions: Higher prenatal exposure to BC, closer residential proximity to road major roadways, and higher traffic density were all associated with earlier age at menarche. The 3rd prenatal trimester and the window around birth may be especially important for traffic-related endocrine-disrupting and pro-inflammatory exposures with potential to accelerate puberty timing among females. Presentation: 6/1/2024

A systematic review on the impact of SARS-CoV-2 viral infection on precocious puberty

Precocious puberty is defined as the onset of sexual characteristics before age 8 in girls and 9 in boys, with serious physical and psychological implications, including advanced bone maturation, early growth cessation, and increased behavioral issues. As per the studies done by Gupta et al precocious puberty cases have risen during the pandemic, prompting inquiries into the potential link between SARS-CoV-2 and early pubertal onset. PubMed, Scopus Web of Science, Google Scholar, and other electronic databases were used for the literature search. The search was restricted to studies published between January 2020 and July 2024. The study has shown a concerning increase in precocious puberty cases during the pandemic, with reports of a significant rise ranging from 9.8% to 93%. The increase clearly shows the concern of having a massive impact on the puberty timing in girls. The data reveal a consistent increase in the incidence of precocious puberty during the pandemic, with relative increases ranging from 0.2 average incidence per month pre-pandemic to 5.9 average per month pandemic incidence. These findings underscore the need for localized public health strategies and further research to fully understand the long-term implications of early puberty in the context of the COVID-19 pandemic. This review emphasizes the importance of continued monitoring and research to mitigate the potential long-term health risks associated with precocious puberty, including metabolic, cardiovascular, and psychological disorders.

Comparative study of the growth, stress status and reproductive capabilities of four wild-type zebrafish (Danio rerio) lines

BackgroundZebrafish are widely used in various research fields and to fulfil the diverse research needs, numerous zebrafish lines are available, each with a unique domestication background, potentially resulting in intraspecies differences in specific biological functions. Few studies have compared multiple zebrafish lines under identical conditions to investigate both inter- and intra-line variability related to different functions. However, such variability could pose a challenge for the reproducibility of results in studies utilising zebrafish, particularly when the line used is not clearly specified. This study assessed growth, stress status (cortisol, serotonin) and reproductive capabilities (maturity, fecundity, fertilisation rate, sperm quality) of four commonly used wild-type zebrafish lines (AB, SJD, TU, WIK) using standardized protocols.ResultsThe stress markers levels were found to be similar across the lines, indicating that the endocrine stress status is robust to diverse domestication histories. Variations were observed in the growth and reproductive parameters. The lines exhibited differences in the timing of puberty (86 dpf for AB and SJD lines vs. 107 dpf for the WIK line) despite achieving similar sizes, suggesting that there are line-specific variations in the induction of maturation. Additionally, the AB line demonstrated higher sperm quality than did the other lines and higher fecundity and fertilization rates than did the SJD line. The AB line also exhibiting a smaller adult size but a heavier brain relative to its body weight.ConclusionThese findings emphasize the importance of line selection for zebrafish research, indicating that researchers should consider line-specific traits to ensure the biological relevance and reproducibility of the results.

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.

Diversity of Molecular Functions of RNA-Binding Ubiquitin Ligases from the MKRN Protein Family.

Makorin RING finger protein family includes four members (MKRN1, MKRN2, MKRN3, and MKRN4) that belong to E3 ubiquitin ligases and play a key role in various biological processes, such as cell survival, cell differentiation, and innate and adaptive immunity. MKRN1 contributes to the tumor growth suppression, energy metabolism, anti-pathogen defense, and apoptosis and has a broad variety of targets, including hTERT, APC, FADD, p21, and various viral proteins. MKRN2 regulates cell proliferation, inflammatory response; its targets are p65, PKM2, STAT1, and other proteins. MKRN3 is a master regulator of puberty timing; it controls the levels of gonadotropin-releasing hormone in the arcuate nucleus neurons. MKRN4 is the least studied member of the MKRN protein family, however, it is known to contribute to the Tcell activation by ubiquitination of serine/threonine kinase MAP4K3. Proteins of the MKRN family are associated with the development of numerous diseases, for example, systemic lupus erythematosus, central precocious puberty, Prader-Willi syndrome, degenerative lumbar spinal stenosis, inflammation, and cancer. In this review, we discuss the functional roles of all members of the MKRN protein family and their involvement in the development of diseases.

Neighbourhood environment and early menarche among adolescent girls of five countries

Introduction We aim to investigate the relationship between individuals’ perceptions of their neighbourhood environment and early menarche. Methods This was a retrospective cohort study of 7,486 girls of Ethiopia, India, South Korea, the United Kingdom (UK), and the United States (US), born in 1997–2011 was analysed. Early menarche was defined as being below the 10th to 20th percentiles in each cohort, considering the varying distributions across countries. Perceived neighbourhood environments were assessed based on the responses for neighbourhood pollution, safety, and recreational facilities. We calculated the relative risk (RR) of early menarche for unfavourable environment. Results The mean age at menarche was lowest in South Korea (10.6 years) and highest in Ethiopia (13.7 years). Unfavourable environment was associated with higher risk of early menarche overall (RR = 1.34, 95% confidence interval [CI]:1.09–1.65) and each country (3.03, 95% CI: 1.15–7.96 in Ethiopia; 1.99, 95% CI: 0.97–4.10 in India, 1.23, 95% CI: 0.67–2.27 in Korea; 1.26, 95% CI: 0.96–1.64 in the UK). Specifically, pollution (1.29, 95% CI: 1.03–1.62) and low safety (1.19, 95% CI: 1.60–1.88) were associated with early menarche. Conclusions Our finding highlights the potential role of perceived neighbourhood environment in the timing of puberty.

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.

Phylogenomic analyses of all species of swordtail fishes (genus Xiphophorus) show that hybridization preceded speciation

Hybridization has been recognized to play important roles in evolution, however studies of the genetic consequence are still lagging behind in vertebrates due to the lack of appropriate experimental systems. Fish of the genus Xiphophorus are proposed to have evolved with multiple ancient and ongoing hybridization events. They have served as an informative research model in evolutionary biology and in biomedical research on human disease for more than a century. Here, we provide the complete genomic resource including annotations for all described 26 Xiphophorus species and three undescribed taxa and resolve all uncertain phylogenetic relationships. We investigate the molecular evolution of genes related to cancers such as melanoma and for the genetic control of puberty timing, focusing on genes that are predicted to be involved in pre-and postzygotic isolation and thus affect hybridization. We discovered dramatic size-variation of some gene families. These persisted despite reticulate evolution, rapid speciation and short divergence time. Finally, we clarify the hybridization history in the entire genus settling disputed hybridization history of two Southern swordtails. Our comparative genomic analyses revealed hybridization ancestries that are manifested in the mosaic fused genomes and show that hybridization often preceded speciation.

Changes in the Bile Acid Pool and Timing of Female Puberty: Potential Novel Role of Hypothalamic TGR5.

The regulation of pubertal timing and reproductive axis maturation is influenced by a myriad of physiologic and environmental inputs yet remains incompletely understood. To contrast differences in bile acid isoform profiles across defined stages of reproductive maturity in humans and a rat model of puberty and to characterize the role of bile acid signaling via hypothalamic expression of bile acid receptor populations in the rodent model. Secondary analysis and pilot studies of clinical cohorts, rodent models, ex vivo analyses of rodent hypothalamic tissues. Bile acid concentrations is the main outcome measure. Lower circulatory conjugated:deconjugated bile acid concentrations and higher total secondary bile acids were observed in postmenarcheal vs pre-/early pubertal adolescents, with similar shifts observed in infantile (postnatal day [PN]14) vs early juvenile (PN21) rats alongside increased tgr5 receptor mRNA expression within the mediobasal hypothalamus of female rats. 16S rRNA gene sequencing of the rodent gut microbiome across postnatal life revealed changes in the gut microbial composition predicted to have bile salt hydrolase activity, which was observed in parallel with the increased deconjugated and increased concentrations of secondary bile acids. We show that TGR5-stimulated GnRH release from hypothalamic explants is mediated through kisspeptin receptors and that early overexpression of human-TGR5 within the arcuate nucleus accelerates pubertal onset in female rats. Bile acid isoform shifts along stages of reproductive maturation are conserved across rodents and humans, with preclinical models providing mechanistic insight for the neuroendocrine-hepatic-gut microbiome axis as a potential moderator of pubertal timing in females.

Improving the Quality of Life of Women Living with Asthma: A Clarion Call for Nurse Entrepreneurs (Nurseprenuers)

Asthma is a chronic lung disease with episodes of wheezing, breathlessness, tightness in the chest, or coughing etc. Among the general population, asthma prevalence is higher in women than men. However, several clinical studies point to distinctive changes in the prevalence and severity of asthma with age. Male children have asthma more frequently. however, in and around the time of puberty, there is a reversal of this incidence and a female predominance exists. Women with asthma may have more symptoms during certain times in the menstrual cycle and it may cause problems also during pregnancy. Evidence from several studies suggests the role of anatomical structure and sex hormones in exacerbation of asthma in females. With the knowledge of the role of anatomical structure and hormones of adult female in asthma flare-ups, exacerbation and quality of life, it should be assumed that there should be a clear difference in the management of asthma in the both genders. However, this is not so, as there is no difference in the management of asthma in male and female. There is need for policy making that will enhance the quality of life of female living with asthma and need for nurseprenuers to take up this challenge of relieving the burden of adult female living with asthma through social support by establishing female base asthma organizations or liaising with existing ones to establish a female unit that will improve the quality of life of adult females living with asthma.

Vgll3 regulates the timing of puberty in farmed Atlantic salmon, but it does not explain family discordance in male maturation following different smolt production regimes

Atlantic salmon (Salmo salar) farming is moving towards extended periods of land-based production to minimise the time at sea, but this increases the risk of unwanted male sexual maturation. As the timing of puberty is driven by genetics (e.g. vgll3) and the environment, optimising rearing strategies and broodstock management may help alleviate the problem. Subsequently, we used a domesticated strain of vgll3 heterozygous broodstock to produce three all-male half-sibling families using three different production regimes to assess the timing of first puberty. Firstly, “large smolts” were produced in a flow-through system on 13 °C freshwater and constant light from first feeding (day 0) up to 1 kg (day 354). The mean incidence of pubertal males increased from 2% at 30 g, up to 78% at 1 kg. Genetics explained a significant (p < 0.05) amount of the variation, with 93, 71, and 34% of the expected early, intermediate, and late maturing vgll3 genotypes being pubertal on day 354, respectively. In addition, pubertal males in the early vgll3 genotype were found at the first sampling at ≈30 g, while it was not observed in the heterozygous and late genotypes until the fish were ≈90 g and ≈280 g, respectively. Secondly, “post-smolts” were produced by switching half the large smolts to 13 °C seawater at 420 g (day 272) and growing them in tanks to 0.95 kg (day 354). This led to a significant 14% reduction in the total incidence of puberty by day 354 compared to the large smolts. However, the regulation of pubertal timing by vgll3 did not interact with salinity. Thirdly, traditional “under-yearling” smolts were produced using periods of natural or manipulated temperature and photoperiod, followed by transfer to a sea-cage at 150 g in December (day 290) where they stayed for one year until harvest at 4.75 kg (day 648). None of these fish were mature at sea transfer, but 9% were at harvest, with 22, 7, and 2% of the early, intermediate, and late vgll3 genotypes being mature, respectively. When comparing the regimes, family effects outside of vgll3 on the prevalence of sexual maturation were significant for the land-based regimes (family means from 46 to 93% on day 354), but not in sea-cages (family means from 7 to 11% on day 648) and evidence for either vgll3 allele being dominant was mixed. Vgll3 also had minimal effects on body size/growth in any regime/family. In conclusion, i) selecting for the late vgll3 allele is an effective method to delay puberty over a range of production regimes, ii) family effects outside of vgll3 were not consistent across regimes, and iii) using seawater reduced the incidence of precocious puberty during land-based production.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Frequency of Delayed Puberty in Boys with Contemporary Management of Duchenne Muscular Dystrophy.

Delayed puberty is thought to be common in boys with Duchenne muscular dystrophy (DMD) treated with long term oral glucocorticoid. This study aims to report the frequency of delayed puberty in DMD from examination by a paediatric endocrinologist alongside detailed endocrine investigations. All boys with DMD aged at least 14 years in January 2022 known to the paediatric neuromuscular service (2016-2022) were included in this study. Delayed puberty was defined based on testicular volume and genital staging in comparison to published puberty nomogram. Twenty-four out of 37 boys (65%) had evidence of delayed puberty, 23/24 (96%) of those with delayed puberty were on glucocorticoid therapy all of whom were on daily glucocorticoid. On the other hand, 7/13 (54%) of those with normal timing of puberty were on glucocorticoid; 2/7 (29%) were on the intermittent regimen. Of those who were on daily glucocorticoid therapy at the time of assessment of puberty, 23/28 (82%) had evidence of delayed puberty. In boys with delayed puberty, endocrine investigations showed low luteinizing hormone (LH) with undetectable testosterone levels, a pre-pubertal response with lutenizing hormone releasing hormone test and sub-optimal testosterone levels with prolonged human chorionic gonadotropin stimulation. The frequency of delayed puberty in boys with DMD was 65%. Eighty-two percent of adolescent boys with DMD on daily glucocorticoid had evidence of delayed puberty. Biochemical investigations point to functional central hypogonadism in these adolescents. Our data supports the routine monitoring of puberty in boys with DMD.