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Item Associations between menarche-related genetic variants and pubertal growth in male and female adolescents(Elsevier, 2015-01) Tu, Wanzhu; Wagner, Erin K.; Eckert, George J.; Yu, Zhangsheng; Hannon, Tamara; Pratt, J. Howard; He, Chunyan; Department of Epidemiology, School of Public HealthPURPOSE: Previous studies have identified novel genetic variants associated with age at menarche in females of European descent. The pubertal growth effects of these variants have not been carefully evaluated in non-European descent groups. We aimed to examine the effects of 31 newly identified menarche-related single-nucleotide polymorphisms (SNPs) on growth outcomes in African-American (AA) and European-American (EA) children in a prospective cohort. METHODS: We analyzed longitudinal data collected from 263 AAs and 338 EAs enrolled between ages 5 and 17 years; the subjects were followed semiannually for an average of 6 years. The associations between the SNPs and growth-related outcomes, including weight, height, and body mass index (BMI), were examined using mixed-effect models. RESULTS: Longitudinal analyses revealed that 4 (near or in genes VGLL3, PEX2, CA10, and SKOR2) of the 14 menarche-only-related SNPs were associated with changes in weight and BMI in EA and AA (p ≤ .0032), but none of them was associated with changes in height. Of the eight menarche-timing and BMI-related SNPs, none was associated with changes in height, but three (in or near genes NEGR1, ETV5, and FTO) were associated with more rapid increases in weight and/or BMI in EA (p ≤ .0059). Among the nine menarche-timing and height-related SNPs, four (in or near genes ZBTB38, LOC728666, TBX2, and CABLES) were associated with changes in weight or height in EA and AA (p ≤ .0042). CONCLUSIONS: Genetic variants related to age at menarche were found to be associated with various growth parameters in healthy adolescents. The identified associations were often race and sex specific.Item Characterization of Spontaneous and Induced Puberty in Girls with Turner Syndrome(American Association of Clinical Endocrinologists, 2017-07) Folsom, Lisal J.; Slaven, James E.; Nabhan, Zeina M.; Eugster, Erica A.; Medicine, School of MedicineOBJECTIVE: To characterize puberty in girls with Turner syndrome (TS) and determine whether specific patient characteristics are associated with the timing of menarche. We also sought to compare spontaneous versus induced puberty in these patients. METHODS: Medical records of girls followed in our Pediatric Endocrine clinic for TS from 2007 to 2015 were reviewed. RESULTS: Fifty-three girls were included, of whom 10 (19%) achieved menarche spontaneously and 43 (81%) received hormone replacement therapy (HRT). Of girls receiving HRT, a younger age at estrogen initiation correlated with a longer time to menarche (P = .02), and a mosaic karyotype was associated with a shorter time to menarche (P = .02), whereas no relationship was seen for body mass index, estrogen regimen, or maternal age at menarche. Nineteen girls (44%) receiving HRT had bleeding on estrogen alone at a wide dose range and were more likely to be on transdermal than oral preparations (P = .01). Girls with spontaneous puberty achieved menarche at a younger age (P<.01) and were more likely to have mosaic TS (P = .02). CONCLUSION: Significant variability in the timing of menarche exists among girls with TS. However, age at pubertal induction and karyotype were significantly correlated with age at menarche in our patients. A wide range of estrogen doses is seen in girls who bleed prior to progesterone, suggesting extreme variability in estrogen sensitivity among patients with TS. Girls achieving spontaneous menarche are younger and more likely to have a mosaic karyotype than those with induced menarche. Large-scale prospective studies are needed to confirm these results.Item Delay in sexual maturation in perinatally HIV-infected youths is mediated by poor growth(Lippincott, Williams & Wilkins, 2017-06-01) Bellavia, Andrea; Williams, Paige L.; DiMeglio, Linda A.; Hazra, Rohan; Abzug, Mark J.; Patel, Kunjal; Jacobson, Denise L.; Van Dyke, Russell B.; Geffner, Mitchell E.; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P219/219C Study; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of MedicineOBJECTIVE: To evaluate the association between HIV infection and sexual maturation, and mediation of this association by HIV effects on growth. DESIGN: Pooled data were analyzed from two longitudinal cohort studies, the International Maternal Pediatric Adolescent AIDS Clinical Trials P219/219C Study (1993-2007) and the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (2007-2015), including perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youths. METHODS: We evaluated age at sexual maturity among 2539 PHIV and PHEU adolescents based on annual physician-assessed pubertal staging measures. Interval-censored regression models were used to evaluate associations of HIV infection with age at maturity. Mediation analyses accounting for height and BMI Z-scores at specific ages were used to estimate direct and indirect effects of HIV infection on age at sexual maturity. RESULTS: Mean ages at sexual maturity for PHIV girls (n = 1032) were 15.5 years for both female breast and pubic hair and 15.9 and 15.8 years for PHIV boys (n = 1054) for genitalia and pubic hair, respectively. PHIV youths matured approximately 6 months later on average than PHEU (n = 221 girls and 232 boys), and this difference persisted after adjustment for race/ethnicity and birth cohort. BMI and height Z-scores mediated the association between HIV infection and later maturation in girls, accounting for up to 74% of the total HIV effect. Only height Z-scores mediated the effect of HIV on male age at maturity, accounting for up to 98% of the HIV effect. CONCLUSION: PHIV youths attain sexual maturity later on average than PHEU youths. Much of this difference may be attributable to deficient growth, suggesting directions for future interventions.Item Polyciliation of GnRH Neurons in Vivo and in Vitro(Oxford University Press, 2021) Brewer, Kathryn M.; Bansal, Ruchi; Engle, Staci E.; Antonellis, Patrick J.; Cummins, Theodore R.; Berbari, Nicolas F.; Biology, School of SciencePuberty and reproduction are initiated and controlled through the hypothalamic-pituitary-gonadal (HPG) axis. A critical surge of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are released from the anterior pituitary upon release of gonadotrophins from gonadotrophin releasing hormone (GnRH) neurons. Thus, GnRH neurons are key regulators of the HPG axis. GnRH neurons become active when kisspeptin (Kiss1) neuropeptides are released from neurons in the arcuate nucleus. Kiss1 binds to the Kiss1 receptor (Kiss1R), a G-protein coupled receptor (GPCR) which localizes to the primary cilia of GnRH neurons. Loss-of-function mutations of Kiss1R cause hypogonadism in mouse and human models while gain-of-function mutations are associated with precocious puberty. Interestingly, the subset of GnRH neurons that express Kiss1R are observed to be polyciliated, possessing more than one primary cilia, an uncommon property as most neurons only possess a single, primary cilium. The mechanism and conditions leading to GnRH neuron polyciliation are unknown. It is also unclear if multiple cilia impact Kiss1R or other GPCR signaling in these neurons. Here, we utilize cultured mouse primary hypothalamic neurons to begin addressing some of these questions. We have confirmed with qPCR that the ligands GnRH and Kiss1, as well as Kiss1R, are all expressed in these cultures. Surprisingly, when treated with Kiss1 and GnRH ligands we observed a small subset of polyciliated neurons compared to vehicle treated neurons. These observations mirror what is seen during sexual maturation in vivo and suggest that our model system may help elucidate fundamental questions about how ciliary localization of Kiss1r and other GPCRs participate in initiation of puberty and regulation of reproduction. Future studies will focus on the mechanisms of polyciliation and the conditions needed to induce the formation of new cilia in GnRH neurons. Investigating neuronal polyciliation could provide insights into new signaling paradigm in hypogonadism and HPG signaling.Item Progressive skeletal benefits of physical activity when young as assessed at the midshaft humerus in male baseball players(SpringerLink, 2017-07) Warden, Stuart J.; Weatherholt, Alyssa M.; Gudeman, Andrew S.; Mitchell, Drew C.; Thompson, William R.; Fuchs, Robyn K.; Physical Therapy, School of Health and Human SciencesPhysical activity benefits the skeleton, but there is contrasting evidence regarding whether benefits differ at different stages of growth. The current study demonstrates that physical activity should be encouraged at the earliest age possible and be continued into early adulthood to gain most skeletal benefits. INTRODUCTION: The current study explored physical activity-induced bone adaptation at different stages of somatic maturity by comparing side-to-side differences in midshaft humerus properties between male throwing athletes and controls. Throwers present an internally controlled model, while inclusion of control subjects removes normal arm dominance influences. METHODS: Throwing athletes (n = 90) and controls (n = 51) were categorized into maturity groups (pre, peri, post-early, post-mid, and post-late) based on estimated years from peak height velocity (<-2, -2 to 2, 2 to 4, 4 to 10, and >10 years). Side-to-side percent differences in midshaft humerus cortical volumetric bone mineral density (Ct.vBMD) and bone mineral content (Ct.BMC); total (Tt.Ar), medullary (Me.Ar), and cortical (Ct.Ar) areas; average cortical thickness (Ct.Th); and polar Strength Strain Index (SSIP) were assessed. RESULTS: Significant interactions between physical activity and maturity on side-to-side differences in Ct.BMC, Tt.Ar, Ct.Ar, Me.Ar, Ct.Th, and SSIP resulted from the following: (1) greater throwing-to-nonthrowing arm differences than dominant-to-nondominant arm differences in controls (all p < 0.05) and (2) throwing-to-nonthrowing arm differences in throwers being progressively greater across maturity groups (all p < 0.05). Regional analyses revealed greatest adaptation in medial and lateral sectors, particularly in the three post-maturity groups. Years throwing predicted 59% of the variance of the variance in throwing-to-nonthrowing arm difference in SSIP (p < 0.001). CONCLUSION: These data suggest that physical activity has skeletal benefits beginning prior to and continuing beyond somatic maturation and that a longer duration of exposure to physical activity has cumulative skeletal benefits. Thus, physical activity should be encouraged at the earliest age possible and be continued into early adulthood to optimize skeletal benefits.Item Pubertal influences on neural activation during risky decision-making in youth with ADHD and disruptive behavior disorders(Elsevier, 2019-04) Dir, Allyson L.; Hummer, Tom A.; Aalsma, Matthew C.; Hulvershorn, Leslie A.; Pediatrics, School of MedicineOBJECTIVE: Risk-taking during adolescence is a leading cause of mortality; Neuroscience research examining pubertal effects on decision-making is needed to better inform interventions, particularly among youth with attention-deficit/hyperactivity (ADHD) and disruptive behavior disorders (DBD), who are particularly prone to risky decision-making. We examined effects of pubertal development on risky decision-making and neural activation during decision-making among youth with ADHD/DBDs. METHOD: Forty-six 11-12-year-olds (29.4% girls; 54.9% white; Tanner M(SD) = 2.08(1.32)) who met DSM-5 criteria for ADHD/DBD completed the Balloon Analog Risk Task (BART) during fMRI scanning. We examined effects of Tanner stage, sex, and age on risky decision-making (mean wager at which individuals stopped balloon inflation) and neural activation in the middle frontal gyrus and the ventral striatum during the choice and outcome phases of decision-making. RESULTS: Those in earlier pubertal stages made riskier decisions during the BART compared to those in later Tanner stages (β=-0.62, p = .02). Later pubertal stage was associated with greater activation in the left middle frontal gyrus (β=0.61, p = .03) during the choice phase and in the right ventral striatum in response to rewards (β=0.59, p = .03). CONCLUSION: Youth with ADHD/DBD in later stages of puberty, regardless of age, show greater ventral striatal activation in response to rewards.Item Pubertal maturation and weight status are associated with dyslipidemia among children and adolescents in Northwest China(Nature Publishing Group, 2020-10-01) Cao, Juan; Zhang, Ling; Li, Jing; Sun, Lijiao; Liu, Shanghong; Zhang, Jianjun; Zhao, Haiping; Epidemiology, School of Public HealthDyslipidemia is one of major risk factors for cardiovascular disease. The early detection and treatment of dyslipidemia can reduce cardiovascular disease risk. A cross-sectional study was carried out in Ningxia, China to determine the prevalence of dyslipidemia and its association with body mass index (BMI) and pubertal stage. A total of 1783 students were selected from middle schools and high schools in September 2014 using stratified random cluster sampling. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured by using MOL-300 automatic biochemical analyzer with associated kits. The prevalence of adolescents with one abnormal serum lipid component was 43.2% and was significantly different across three pubertal stages (p < 0.0001). The abnormal rates of HDL-C and TG increased as the students maturated through the early, middle, and late stages of puberty (all p < 0.0001). Similar results were obtained when separate analyses were performed for boys and girls. In linear regression analysis, BMI was positively associated with serum levels of TC, LDL-C, and TG, but inversely associated with serum levels of HDL-C after the adjustment for age, sex, and race. In multivariable logistic regression analysis, obesity was associated with an increased risk of developing high TC, while pubertal maturation was associated with an elevated risk of experiencing low HDL-C and high TG (all p < 0.05). In conclusions, dyslipidemia is common in an adolescent population of Northwest China and its prevalence rates substantially vary with weight status and pubertal stage.Item The Variability of Growth and Puberty in Growth Hormone-treated Children Born Small for Gestational Age(The Endocrine Society, 2022) Saroufim, Rita; Fuqua, John S.; Pediatrics, School of Medicine