Pubertal timing in boys and girls born to mothers with gestational diabetes mellitus: a systematic review

Context The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity. Objective To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM. Data sources We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019. Study selection and extraction Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described as reported in the primary studies. Results Seven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo. Conclusions Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

A longitudinal analysis of puberty-related cortical development

The brain undergoes extensive structural changes during adolescence, concurrent to puberty-related physical and hormonal changes. While animal research suggests these biological processes are related to one another, our knowledge of brain development in humans is largely based on age-related processes. Thus, the current study characterized puberty-related changes in human brain structure, by combining data from two longitudinal neuroimaging cohorts. Beyond normative changes in cortical thickness, we examined whether individual differences in the rate of pubertal maturation (or “pubertal tempo”) was associated with variations in cortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age, as well as questionnaire assessments of pubertal stage at each wave. Generalized additive mixture models were used to characterize trajectories of cortical development. Results revealed widespread linear puberty-related changes across much of the cortex. Many of these changes, particularly within the frontal and parietal cortices, were independent of age-related development. Males exhibiting faster pubertal tempo demonstrated greater thinning in the precuneus and frontal cortices than same-aged and -sex peers. Findings suggest that the unique influence of puberty on cortical development may be more extensive than previously identified, and also emphasize important individual differences in the coupling of these developmental processes.

Pubertal timing and breast cancer risk in the Sister Study cohort

Background Earlier age at menarche is an established risk factor for breast cancer. While age at menarche has been fairly stable over the past half-century, age at breast development (thelarche) has continued to decrease. Recently, earlier age at thelarche and a longer time between thelarche and menarche (pubertal tempo) were shown to be associated with increased breast cancer risk. Our objective was to examine how breast cancer risk was associated with pubertal timing and tempo in a prospective US cohort. Methods Women ages 35–74 years without a history of breast cancer, but who had a sister previously diagnosed with breast cancer, were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported their ages at thelarche and menarche. Pubertal tempo was age at menarche minus age at thelarche. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each pubertal milestone and risk of breast cancer (invasive or ductal carcinoma in situ) using Cox proportional hazards regression. We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight at age 10, and extent of breast cancer family history, as characterized by a Bayesian score based on first-degree family structure. Results During follow-up (mean = 9.3 years), 3295 eligible women were diagnosed with breast cancer. Early ages at thelarche (HR = 1.23, 95% CI 1.03–1.46 for < 10 vs. 12–13 years) and menarche (HR = 1.10, 95% CI 1.01–1.20 for < 12 vs. 12–13 years) were positively associated with breast cancer risk. Pubertal tempo was not associated with breast cancer risk (HR = 0.99, 95% CI 0.97–1.02 per 1-year longer tempo). When considering early thelarche (< 10 years) and early menarche (< 12 years) jointly, women with both had a 30% greater risk of breast cancer compared with women with neither risk factor (95% CI 1.07–1.57). The association between age at thelarche and breast cancer risk did not significantly vary by birth cohort, race/ethnicity, childhood weight, or Bayesian family history score. Conclusions Earlier ages at thelarche and menarche may enhance susceptibility to breast carcinogenesis. Age at thelarche is an important risk factor to consider given secular trends towards earlier development.

Early Life Stress, Frontoamygdala Connectivity, and Biological Aging in Adolescence: A Longitudinal Investigation

Early life stress (ELS) may accelerate frontoamygdala development related to socioemotional processing, serving as a potential source of resilience. Whether this circuit is associated with other proposed measures of accelerated development is unknown. In a sample of young adolescents, we examined the relations among ELS, frontoamygdala circuitry during viewing of emotional faces, cellular aging as measured by telomere shortening, and pubertal tempo. We found that greater cumulative severity of ELS was associated with stronger negative coupling between bilateral centromedial amygdala and the ventromedial prefrontal cortex, a pattern that may reflect more mature connectivity. More negative frontoamygdala coupling (for distinct amygdala subdivisions) was associated with slower telomere shortening and pubertal tempo over 2 years. These potentially protective associations of negative frontoamygdala connectivity were most pronounced in adolescents who had been exposed to higher ELS. Our findings provide support for the formulation that ELS accelerates maturation of frontoamygdala connectivity and provide novel evidence that this neural circuitry confers protection against accelerated biological aging, particularly for adolescents who have experienced higher ELS. Although negative frontoamygdala connectivity may be an adaptation to ELS, frontoamygdala connectivity, cellular aging, and pubertal tempo do not appear to be measures of the same developmental process.

Pubertal timing in boys and girls born to mothers with gestational diabetes mellitus: a systematic review

ABSTRACTContextThe incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.OjectiveTo evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.Data SourcesWe searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.Study selection and extractionTwo reviewers independently selected studies, collected data and appraised study quality. Results were tabulated and narratively described as reported in the primary studies.ResultsSeven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.ConclusionsPubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

Pubertal timing and breast density in young women: a prospective cohort study

Background Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. Methods From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006–2008, 182 participants then aged 25–29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. Results The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2–86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2–26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9–17.5%)). Conclusions Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones

Context The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. Objective We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. Design and Setting Longitudinal observational study. Participants and Main Outcome Measures In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. Results Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. Conclusions Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.

3520 Neural connectivity mechanisms linking off-time pubertal development and depression risk in adolescence

OBJECTIVES/SPECIFIC AIMS: Earlier pubertal timing has been associated with risk for depression, particularly in girls (e.g., Keenan etal., 2014). Evidence suggests pubertal timing in girls also relates to alterations in the microstructural properties of brain white matter tracts in late adolescence (Chahal etal., 2018), and structural connectivity of cingulate and frontal regions (Chahal etal., in prep), though differences in pubertal development in both boys and girls have not been examined in the context of brain functional connectivity (FC). Individual differences in the course of puberty may have enduring effects on functional coupling among brain regions that may contribute to the risk for psychopathology. To address this question, we explored the relation between pubertal timing and tempo with depression symptoms (age 16). Then, we examined whether brain network FC (age 16) associates with pubertal indices and predicts concurrent and later depressive symptoms (age 18). METHODS/STUDY POPULATION: Sixty-eight adolescents (37 females) completed the Mini-Mood and Anxiety Symptom Questionnaire (MASQ; Clark & Watson, 1995) at ages 14-18. Gompertz growth curve modelling of pubertal development (age 10-15; Waves 1-6) was used to estimate pubertal timing and tempo per individual, separately for males and females (e.g., Chahal etal., 2018). Resting-state MRI data (age 16) were parcellated into 264 cortical and subcortical regions to create region-to-region FC matrices based on correlations of time-series. Individual matrices were fed to the GraphVar program (Kruschwitz etal., 2015) to assess the interaction of pubertal timing and pubertal tempo with functional network connectivity using Network-based statistic (NBS; Zalesky etal., 2010). Subnetworks showing alterations in relation to pubertal timing and tempo were then examined in association with concurrent (age 16) symptoms and used to predict future depressive symptoms (age 18). RESULTS/ANTICIPATED RESULTS: In all youth, earlier pubertal timing was associated with higher depressive symptoms at age 16 (p<.018). This association was stronger in girls with slower pubertal tempo (p<.039). Interregional connectivity analyses revealed that the interaction of earlier pubertal timing and slower tempo was associated with lower FC between the left cingulate gyrus and right precuneus (p<.0001), regions implicated in emotion processing (i.e., Affective Processing Network) and self-referential thinking (i.e., Default Mode Network). FC of the three other emotion- and self-referential processing network regions (i.g., left insula, superior parietal lobule, and precuneus) was lower in youth with greater age 16 depressive symptoms (p<.0001). Finally, lower FC of of the left and right inferior parietal lobule predicted greater depressive symptoms at age 18 (p<.0001). In summary, FC of overlapping affective and default mode network areas was related to earlier pubertal timing and higher concurrent and future depressive symptoms. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings demonstrate individual differences in pubertal maturation are associated with depressive symptoms and differences in brain connectivity in mid-adolescence. Early pubertal development was associated with greater depression symptoms and lower FC of brain regions involved in emotion regulation and self-referential processing. Further, FC between these regions predicted higher depression symptoms two years later. These neurobiological mechanisms may, in part, underlie the link between off-time pubertal development and the risk for depression. These findings also have important implications for precision psychiatry, as we show that a risk-factor of depression (early pubertal timing) may manifest in developing neurobiology in region-specific ways. Previous network models of depression (e.g., Li etal., 2018) implicated affective network connectivity in sustained negative mood and the default mode/ self-referential network in rumination. Other networks implicated in these past models include the reward network, which may be involved in anhedonia and loss of pleasure. Our study only found associations between affective and self-referential regional connectivity, pubertal maturation, and depression, suggesting that pubertal risk factors may relate more closely with emotion-regulation and self-referential processing deficits.

Growth trajectory and pubertal tempo from birth till final height in a girl with Wolf-Hirschhorn syndrome

Summary Growth anomaly is a prominent feature in Wolf-Hirschhorn syndrome (WHS), a rare congenital disorder caused by variable deletion of chromosome 4p. While growth charts have been developed for WHS patients 0–4 years of age and growth data available for Japanese WHS patients 0–17 years, information on pubertal growth and final height among WHS children remain lacking. Growth hormone (GH) therapy has been reported in two GH-sufficient children with WHS, allowing for pre-puberty catch up growth; however, pubertal growth and final height information was also unavailable. We describe the complete growth journey of a GH-sufficient girl with WHS from birth until final height (FH), in relation to her mid parental height (MPH) and target range (TR). Her growth trajectory and pubertal changes during childhood, when she was treated with growth hormone (GH) from 3 years 8 months old till 6 months post-menarche at age 11 years was fully detailed. Learning points: Pubertal growth characteristics and FH information in WHS is lacking. While pre-pubertal growth may be improved by GH, GH therapy may not translate to improvement in FH in WHS patients. Longitudinal growth, puberty and FH data of more WHS patients may improve the understanding of growth in its various phases (infancy/childhood/puberty).