scholarly journals Age at onset of different pubertal signs in boys and girls and differential DNA methylation at age 10 and 18 years: an epigenome-wide follow-up study

2020 ◽  
Vol 2020 (2) ◽  
Author(s):  
Su Chen ◽  
Hala Refaey ◽  
Nandini Mukherjee ◽  
Farnaz Solatikia ◽  
Yu Jiang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
North America ◽  
Pubertal Development ◽  
Age At Onset ◽  
Breast Development ◽  
Growth Spurt ◽  
Biological Processes ◽  
Pubertal Onset ◽  
Cpg Site

Abstract STUDY QUESTION Is the age of onset of pubertal markers related to subsequent changes in DNA methylation (DNAm)? SUMMARY ANSWER We identified 273 cytosine-phosphate-guanine (CpG) dinucleotides in girls and 67 CpGs in boys that were related to puberty and that were replicable in two other investigations. WHAT IS KNOWN ALREADY Previously, 457 CpGs (not gender-specific) and 347 (in girls) and 50 (in boys), respectively, were found to be associated with puberty, according to investigations of studies from Denmark (20 girls and 31 boys) and North America (30 girls and 25 boys). STUDY DESIGN, SIZE, DURATION The study was based on a birth cohort of 1456 participants born in 1989/90, with follow-up at age 10 and 18 years. PARTICIPANTS/MATERIALS, SETTING, METHODS The follow-up included 470 participants with information on DNAm and age of pubertal onset (244 girls and 226 boys). Age of pubertal onset was ascertained retrospectively at age 18 years. Using the Pubertal Development Scale, both genders were asked about ages of onset of growth spurt, body hair growth and skin changes. Ages at voice deepening and growth of facial hair were inquired from boys; ages at breast development and menarche from girls. Blood samples were collected at 10 and 18 years of age. DNA was extracted using a standard salting out procedure. The methylation level for each CpG site was assessed using one of two different platforms. DNAm was measured by a ratio of intensities denoted as β values for each CpG site. After quality control, 349 455 CpG sites were available for analysis. M values were calculated (log2(β/(1−β)) to approximate a normal distribution, and their levels were adjusted for blood cell proportions. Linear mixed models were applied to test the association between age of pubertal markers and repeated measurement of DNAm at 10 and 18 years. MAIN RESULTS AND THE ROLE OF CHANCE In girls, a total of 63 019 CpGs statistically significantly changed after occurrence of any of the five pubertal events and 13 487 were changed subsequent to all five events: the respective number is boys were 3072 and 301. To further exclude false-positive findings, we investigated which CpGs were replicable in prior studies from Denmark or North America, resulting in 273 replicable CpG in girls and 67 CpGs in boys (236 and 68 genes, respectively). Most identified genes are known to be related to biological processes of puberty; however, genetic polymorphisms of only four of these genes were previously linked to pubertal markers in humans. LIMITATIONS, REASONS FOR CAUTION The relative age of pubertal onset to the age of DNAm measurements does not allow causal inference, since DNAm at an earlier age may have affected the pubertal age or pubertal age may have altered later DNAm. This investigation concentrates on autosomes. CpGs on X and Y chromosomes are not included in the current study. WIDER IMPLICATIONS OF THE FINDINGS Assessment of biological processes involved in pubertal transitions should include epigenetic information. Differential DNAm related to puberty needs to be investigated to determine whether it can act as an early marker for adult diseases known to be associated with puberty. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by NIH grants R03HD092776 (Epigenetic characterization of pubertal transitions) and R01AI121226. The 10-year follow-up of this study was funded by National Asthma Campaign, UK (Grant No 364), and the 18-year follow-up by a grant from the National Heart and Blood Institute (R01 HL082925). The authors have no conflicts to report.

scholarly journals Accuracy of Doppler Assessment of the Uterine Arteries in Healthy Girls for the Diagnosis of Pubertal Onset

2021 ◽  
Author(s):  
Amanda Cheuiche ◽  
Letícia Guimarães da Silveira ◽  
Gustavo Monteiro Escott ◽  
Iara Regina Siqueira Lucena ◽  
Márcia Puñales ◽  
...  
Keyword(s):  
Uterine Artery ◽  
Pubertal Development ◽  
Doppler Imaging ◽  
Breast Development ◽  
Youden Index ◽  
Pelvic Ultrasound ◽  
Roc Curve Analysis ◽  
Pubertal Onset ◽  
Uterine Arteries ◽  
Uterine Volume

Abstract Purpose: To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls. Methods: Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis. Results: We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a significantly higher mean PI (mean, 6.70; SD, 2.15) than girls in initial puberty (mean, 4.14; SD, 1.55) and in late puberty (mean, 2.81; SD, 1.05) (P<0.001 for all comparisons), which reflects a progressive increase in blood flow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 (SD, 0.04) (P<0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI <5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, specificity of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty. Conclusions: The significant reduction in the PI during pubertal development combined with increasing uterine volume can be a valuable, highly specific, noninvasive tool to confirm the onset of puberty.

scholarly journals Evaluation and significance of the degree of pituitary-gonadal inhibition during intranasal administration of buserelin

1987 ◽  
Vol 116 (4) ◽  
pp. 519-525 ◽  
Author(s):  
J. P. Bourguignon ◽  
C. Heinrichs ◽  
G. Van Vliet ◽  
M. Vandeweghe ◽  
M. Vanderschueren-Lodeweyckx ◽  
...  
Keyword(s):  
Intranasal Administration ◽  
Pubertal Development ◽  
Age At Onset ◽  
Central Precocious Puberty ◽  
Bone Age ◽  
Height Velocity ◽  
Breast Development ◽  
Variable Degree ◽  
Oestradiol Level ◽  
Serum Lh

Abstract. In 12 patients (11 girls, 1 boy) with central precocious puberty and 4 patients (3 girls, 1 boy) with idiopathic short stature treated for 1 year with a GnRH superagonist, buserelin (0.3 mg intranasally, 4 times a day), a variable degree of inhibition of sex steroid secretion and pubertal development was observed. Regression of breast or genital development required a daily dosage of buserelin ≥ 34 μg/kg. After 3, 6, 9 and 12 months of treatment, the serum oestradiol level in the girls was positively related (r = 0.69) to basal serum LH measured at the same time and to change in breast development during the previous 3 months. In contrast, LH response to GnRH was very low in all the patients and not related to the degree of oestradiol inhibition. Height velocity and bone age velocity during the year of treatment showed no significant correlation with mean oestradiol level. Bone age velocity during treatment was inversely related to bone age at onset of buserelin. These data show that 1) the pituitary gonadal suppression during intranasal administration of buserelin is variable and dose-dependent; 2) gonadotropin response to GnRH is not a sensitive indicator of incomplete pituitary suppression during buserelin treatment; and 3) bone age velocity during treatment is more reduced the more advanced bone age is at onset of treatment.

Psychological Effects of Precocious and Delayed Puberty

2010 ◽  
Author(s):  
Laura M. Derose ◽  
Julia A. Graber
Keyword(s):  
African American ◽  
Pubertal Development ◽  
Pubic Hair ◽  
Breast Development ◽  
Delayed Puberty ◽  
Sex Characteristics ◽  
African American Girls ◽  
Pubertal Onset ◽  
The Mean ◽  
Hair Development

The timing of pubertal onset is marked by substantial variability within the range of normative development. Pubertal onset has mainly been measured by appearance of secondary sex characteristics—pubic hair development across sexes, and breast development in girls and testicular development in boys. This chapter provides statistics for the average age of pubertal onset, including findings for how average age differs by race. The two major types of pubertal disorders, precocious puberty and delayed puberty, are described, with a brief synopsis of the possible causes (for a comprehensive review of medical causes, see Grumbach and Styne 2003). The major focus of the chapter is on the psychological and behavioral consequences of precocious and delayed puberty. Although the majority of research on this topic has included nonclinical samples (onset or delay of puberty nearing 2 standard deviations [SD] from the mean), findings would be applicable to children who exhibit clinical precocious or delayed puberty (onset or delay of puberty >2 SDs from the mean). Finally, the chapter reviews the clinical practices for “treating” puberty that is normative by pediatric standards. Breast budding is generally the first sexual characteristic to appear in females, and is most commonly classified by Marshall and Tanner’s (1969) five stages of development. Breast development begins in the United States between ages 8 and 13, with a mean age of 9.96 for Caucasian girls and a mean age of 8.87 for African American girls (Herman-Giddens et al. 1997). Pubic hair development typically begins shortly after breast budding; however approximately 20 percent of girls experience pubic hair development prior to breast budding (Brooks-Gunn and Reiter 1990). Pubic hair development also begins between the ages of 8 and 13 years, with a mean age 10.5 years in Caucasian girls and 8.8 years for African American girls (Herman-Giddens et al. 1997). Menarche is a late sign of pubertal development in girls and occurs following the peak in height velocity and during the rapid increase in weight and body fat (Tanner 1978). The mean age of menarche in North America is 12.88 years for Caucasian girls and 12.16 years for African American girls (Herman-Giddens et al. 1997).

scholarly journals Pubertal Onset in Boys and Girls Is Influenced by Pubertal Timing of Both Parents

2016 ◽  
Vol 101 (7) ◽  
pp. 2667-2674 ◽  
Author(s):  
Christine Wohlfahrt-Veje ◽  
Annette Mouritsen ◽  
Casper P. Hagen ◽  
Jeanette Tinggaard ◽  
Mikkel Grunnet Mieritz ◽  
...  
Keyword(s):  
Pubertal Timing ◽  
Pubertal Development ◽  
Age At Onset ◽  
Pubic Hair ◽  
Healthy Children ◽  
Pubertal Onset ◽  
Hair Development ◽  
The Impact ◽  
Age Of Menarche ◽  
Menarche Age

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 &gt;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.

The Interaction of Pubertal and Psychosocial Development During Adolescence

1991 ◽  
Vol 12 (8) ◽  
pp. 249-255
Author(s):  
Iris F. Litt
Keyword(s):  
Psychosocial Development ◽  
Developmental Process ◽  
Pubertal Development ◽  
Breast Development ◽  
Growth Spurt ◽  
Sex Characteristics ◽  
Hormonal Changes ◽  
Secondary Sex Characteristics ◽  
Is Development ◽  
Physical Changes

During the second decade of life, the physical changes of puberty interact with those of psychosocial and cognitive development to forge the young adult, who often bears little resemblance to the same individual as a child. This article reviews those elements of the developmental process that have an impact on the physician's ability to understand and care for the adolescent patient. PUBERTY Endocrine Changes Release of inhibition on the hypothalamus unleashes an outpouring of releasing hormones, which stimulate the secretion of gonadotropins and growth hormone by the pituitary. These are produced in a sleep-augmented, pulsatile fashion that characterizes the onset of pubertal development. As a result, within the few years between the onset and completion of puberty, levels of estradiol increase eightfold in females, and levels of testosterone increase 18-fold in males. These hormonal changes stimulate the growth spurt and development of secondary sex characteristics. Development of Secondary Sex Characteristics Breast Development. In females, one of the earliest signs of puberty is development of the breast bud. The subsequent progression of breast development is orderly and predictable, thus forming one of the bases for the categorization in females of the stages of puberty, often referred to as Tanner stages or SMRs (sex maturity ratings).

scholarly journals Outcomes of pubertal development in girls as a function of pubertal onset age

2018 ◽  
Vol 179 (5) ◽  
pp. 279-285 ◽  
Author(s):  
A German ◽  
M Shmoish ◽  
J Belsky ◽  
Z Hochberg
Keyword(s):  
Youth Development ◽  
Late Onset ◽  
Pubertal Development ◽  
Age At Onset ◽  
Tanner Stage ◽  
Pubic Hair ◽  
Onset Age ◽  
Pubertal Onset ◽  
Pubertal Growth ◽  
Early Child Care

Background The relationship between pubertal onset and tempo and pubertal growth is controversial. We hypothesized that the age at onset of girls’ puberty predicts pubertal tempo and the rate of pubertal progression. Methods We analyzed the data of 380 girls from the prospective Study of Early Child Care and Youth Development (SECCYD) who were recruited in the USA from 1991 to 2006 and followed from birth to age 15.5 years. We used the following indicators: thelarche age (Tanner stage B2), pubarche age (P2), menarche age (M), the age when breast (B5) and pubic hair (P5) became fully mature, pubertal growth, pubertal duration (time from B2 to B5) and pubertal progression (time from B2 to M). We clustered the girls according to B2 age into early onset (EO; <9.4 years), intermediate (IO; 9.4–10.5 years), late onset (LO; >10.5 years). Results All indicators of pubertal onset and conclusion occurred earlier in the EOs than in the LOs; yet, the differences in the age at main pubertal milestones lessened as puberty progressed: 2 years for B2; −1.4 years for M; −1 year for B5. In EOs, puberty was 1 year (average) longer than in LOs. Although EOs grew 7 cm (average) more than LOs, their heights at B5 were comparable. There was a significant relationship between the thelarche age and puberty tempo (r = 0.23, P < 0.0001). Conclusions The study highlights the predictive nature of variation in the onset age of puberty on its progression and duration. These results are reassuring in this context and will add to clinicians’ and parental understanding of the expected milestones of puberty.

scholarly journals Worldwide Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls

2020 ◽  
Vol 174 (4) ◽  
pp. e195881 ◽  
Author(s):  
Camilla Eckert-Lind ◽  
Alexander S. Busch ◽  
Jørgen H. Petersen ◽  
Frank M. Biro ◽  
Gary Butler ◽  
...  
Keyword(s):  
Secular Trends ◽  
Breast Development ◽  
Pubertal Onset

scholarly journals VTRNA2-1: Genetic Variation, Heritable Methylation and Disease Association

2021 ◽  
Vol 22 (5) ◽  
pp. 2535
Author(s):  
Pierre-Antoine Dugué ◽  
Chenglong Yu ◽  
Timothy McKay ◽  
Ee Ming Wong ◽  
Jihoon Eric Joo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Genetic Variation ◽  
Genetic Factors ◽  
Disease Association ◽  
Country Of Birth ◽  
Cpg Site ◽  
Multiple Case ◽  
Metastable Epiallele ◽  
Methylation Quantitative Trait Loci

VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 × 10−4); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: −0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.

scholarly journals High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

2021 ◽  
Author(s):  
Katja Bender ◽  
Eilís Perez ◽  
Mihaela Chirica ◽  
Julia Onken ◽  
Johannes Kahn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
World Health ◽  
Central Nervous System Tumor ◽  
High Grade ◽  
Thoracic Spinal Cord ◽  
High Grade Astrocytoma ◽  
Tumor Entity

Abstract Purpose High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

scholarly journals DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Monica del C. Gomez-Alonso ◽  
Anja Kretschmer ◽  
Rory Wilson ◽  
Liliane Pfeiffer ◽  
Ville Karhunen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lipid Metabolism ◽  
Population Based ◽  
Total Serum ◽  
Resonance Spectroscopy ◽  
Metabolic Disturbances ◽  
Cpg Sites ◽  
Gene Transcripts

Abstract Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

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