Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria.

INTRODUCTION: Gender-affirming hormone treatment is known to affect adrenal androgen levels in adult individuals with gender dysphoria (GD). This may be clinically relevant because the adrenal gland plays a critical role in many different metabolic processes. AIM: This study aims to assess the effects of gonadotropin-releasing hormone analogs (GnRHa) treatment and gender-affirming hormone treatment on adrenal androgen levels in adolescents with GD. METHODS: In this prospective study, dehydroepiandrosterone-sulfate (DHEAS) and androstenedione values were measured every 6 months during 2 years of GnRHa treatment only, and 2 years of GnRHa combined with gender-affirming hormone treatment (estradiol or testosterone) in 73 transgirls and 54 transboys. To determine trends in adrenal androgen levels a linear mixed model was used to approximate androgen levels. MAIN OUTCOME MEASURES: DHEAS and androstenedione levels were the main outcome measures. RESULTS: DHEAS levels rose in transboys during GnRHa treatment, which may represent the normal increase during adolescence. In transgirls no change in DHEAS levels during GnRHa treatment was found. Gender-affirming hormone treatment did not affect DHEAS levels in either sex. In transboys androstenedione levels decreased during the first year of GnRHa treatment, which may reflect reduced ovarian androstenedione synthesis, and rose during the first year of gender-affirming hormone treatment, possibly due to conversion of administered testosterone. In transgirls androstenedione levels did not change during either GnRHa or gender-affirming hormone treatment. CLINICAL IMPLICATIONS: No deleterious effects of treatment on adrenal androgen levels were found during approximately 4 years of follow-up. STRENGTHS & LIMITATIONS: This is one of the largest cohort of adolescents with GD, treated using a uniform protocol, with standardized follow-up. The lack of a control group is a limitation. CONCLUSION: The changes in androstenedione levels during GnRHa and gender-affirming hormone treatment in transboys may not be of adrenal origin. The absence of changes in androstenedione levels in transgirls or DHEAS levels in either sex during gender-affirming hormone treatment suggests that gender-affirming hormone treatment does not significantly affect adrenal androgen production. Schagen SEE, Lustenhouwer P, Cohen-Kettenis PT, et al. Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria. J Sex Med 2018;15:1357-1363.

Efficacy and Safety of Pubertal Induction Using 17ß-Estradiol in Transgirls.

Context: Puberty suppression using gonadotropin-releasing hormone agonists, followed by induction of the desired sex characteristics using sex steroids, has been recommended by the current guidelines as the treatment of choice for gender dysphoric adolescents, although little evidence is available. Aim: To evaluate the efficacy and safety of estrogen treatment for pubertal induction in transgirls (female-identifying adolescents assigned male at birth). Methods: Twenty-eight adolescents treated with oral estrogen for ≥1 year were included. The Tanner stage, anthropometry, laboratory parameters, bone age, and body composition were evaluated. Results: Breast development started within 3 months in 83% of adolescents, and after 3 years, 86% had Tanner breast stage 4 to 5. The hip circumference increased and the waist/hip ratio decreased. The median serum estradiol was 100 pmol/L (range, 24 to 380) at the standard adult dose of 2 mg of 17ß-estradiol. The adult height standard deviation score was +1.9 (for females). The body mass index standard deviation score, lean body mass percentage, fat percentage, and blood pressure did not change. No abnormalities of creatinine or liver enzymes were detected, and the hematocrit and hemoglobin A1c did not change. One individual developed hyperprolactinemia during high-dose ethinylestradiol treatment to limit growth. Conclusions: Pubertal induction using estradiol is effective; however, an adult dose of 2 mg does not always result in appropriate serum estradiol levels. Monitoring renal function, liver enzymes, hematocrit, and hemoglobin A1c during pubertal induction with estradiol is not necessary. Further studies are needed to establish effective and safe methods to limit growth.

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

INTRODUCTION: Puberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. AIM: To evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. METHODS: Forty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. MAIN OUTCOME MEASURES: Physical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. RESULTS: GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. CONCLUSION: Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur during GnRHa treatment can be reversed during subsequent cross-sex hormone treatment.

Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density.

BACKGROUND: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. METHODS: Whole-exome sequencing and targeted sequencing were used to detect the LEPR mutations. RNA analysis was performed to assess the effect of splice-site mutations. RESULTS: In 2 unrelated girls with severe obesity, three novel LEPR mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. CONCLUSION: The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology.

Association of the fat mass and obesity-associated gene risk allele, rs9939609A, and reward-related brain structures.

OBJECTIVE: Recently, the fat mass and obesity-associated gene (FTO) has been identified as a genetic risk factor for developing obesity. The underlying mechanisms remain speculative. SNPs within FTO have been associated with brain atrophy in frontal and occipital regions, suggesting that FTO might affect body weight through cerebral pathways. Behavioral studies suggested a relationship between FTO and the reward-related behavioral traits. Therefore the relationship between the FTO risk allele rs9939609A and volumes of reward-related brain structures has been investigated. METHODS: Four hundred and ninety-two Dutch individuals (56% males, age: 70-82 years) participating in the PROSPER study underwent a 3D-T1-weighted MRI to assess the volumes of reward-related brain structures (e.g., amygdala, nucleus accumbens) and of gray matter and white matter. Linear regression analysis was performed to test for the association of subcortical and cortical structures with rs9939609A. RESULTS: rs9939609A is associated with lower volumes of the nucleus accumbens (p=0.03) and trended toward lower cortical gray matter volumes (p=0.08). This association is independent of gender, age, and BMI, FDR corrected. CONCLUSIONS: The FTO risk allele is associated with lower nucleus accumbens volumes, suggesting that the higher body weight of risk-allele carriers might be due to changes within reward-related brain structures.

Using fMRI to Investigate Memory in Young Children Born Small for Gestational Age.

OBJECTIVES: Intrauterine growth restriction (IUGR) can lead to infants being born small for gestational age (SGA). SGA is associated with differences in brain anatomy and impaired cognition. We investigated learning and memory in children born SGA using neuropsychological testing and functional Magnetic Resonance Imaging (fMRI). STUDY DESIGN: 18 children born appropriate for gestational age (AGA) and 34 SGA born children (18 with and 16 without postnatal catch-up growth) participated in this study. All children were between 4 and 7 years old. Cognitive functioning was assessed by IQ and memory testing (Digit/Word Span and Location Learning). A newly developed fMRI picture encoding task was completed by all children in order to assess brain regions involved in memory processes. RESULTS: Neuropsychological testing demonstrated that SGA children had IQ's within the normal range but lower than in AGA and poorer performances across measures of memory. Using fMRI, we observed memory related activity in posterior parahippocampal gyrus as well as the hippocampus proper. Additionally, activation was seen bilaterally in the prefrontal gyrus. Children born SGA showed less activation in the left parahippocampal region compared to AGA. CONCLUSIONS: This is the first fMRI study demonstrating different brain activation patterns in 4-7 year old children born SGA, suggesting that intrauterine growth restriction continues to affect neural functioning in children later-on.

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

New reference charts for testicular volume in Dutch children and adolescents allow the calculation of standard deviation scores.

AIM: Accurate calculations of testicular volume standard deviation (SD) scores are not currently available. We constructed LMS-smoothed age-reference charts for testicular volume in healthy boys. METHODS: The LMS method was used to calculate reference data, based on testicular volumes from ultrasonography and Prader orchidometer of 769 healthy Dutch boys aged 6 months to 19 years. We also explored the association between testicular growth and pubic hair development, and data were compared to orchidometric testicular volumes from the 1997 Dutch nationwide growth study. RESULTS: The LMS-smoothed reference charts showed that no revision of the definition of normal onset of male puberty - from nine to 14 years of age - was warranted. In healthy boys, the pubic hair stage SD scores corresponded with testicular volume SD scores (r = 0.394). However, testes were relatively small for pubic hair stage in Klinefelter's syndrome and relatively large in immunoglobulin superfamily member 1 deficiency syndrome. CONCLUSION: The age-corrected SD scores for testicular volume will aid in the diagnosis and follow-up of abnormalities in the timing and progression of male puberty and in research evaluations. The SD scores can be compared with pubic hair SD scores to identify discrepancies between cell functions that result in relative microorchidism or macroorchidism.

The relationship between moderate-to-vigorous intensity physical activity and insulin resistance, insulin-like growth factor (IGF-1)-system 1, leptin and weight change in healthy women during pregnancy and after delivery.

CONTEXT: Childbearing is considered to be a significant risk factor for developing overweight and obesity. Physical activity might influence weight change via hormonal changes. OBJECTIVE: To test the hypothesis that higher levels of moderate-to-vigorous intensity physical activity (MVPA) are positively associated with maternal insulin sensitivity and reduce IGF-1, IGFBP-3, leptin levels, bodyweight gain/retention and birth weight. METHODS: In healthy nulliparous women, weight measurements were carried out and blood was collected during pregnancy in the 15th, 25th and 35th week, and after delivery at 6, 26 and 52 weeks. At 15 and 35 weeks of pregnancy and 26 weeks postpartum, MVPA was measured using accelerometers. In linear regression models, the relationship between MVPA below or above the median with metabolic and weight outcomes was assessed, adjusted for maternal BMI, age and smoking. RESULTS: Moderate-to-vigorous intensity physical activity (MVPA) decreased significantly during pregnancy, but was very low already in early pregnancy. Insulin resistance and leptin levels increased during pregnancy and decreased significantly after delivery (all P < 0·05). After adjustment, insulin, IGFBP-3 and BMI were significantly lower at 15 weeks of pregnancy in women with MVPA above the median compared to those with MVPA below the median. After 15 weeks of pregnancy, no significant associations were observed between hormonal levels and MVPA. MVPA was neither related to weight retention, nor to birth weight. CONCLUSION: Except in early pregnancy, MPVA was not related to metabolic outcomes. In addition, MVPA during pregnancy was not related to weight retention or birth weight.

Effect of the Go4it multidisciplinary group treatment for obese adolescents on health related quality of life: a randomised controlled trial.

BACKGROUND: We developed a Dutch outpatient multidisciplinary group treatment (Go4it) for obese adolescents, including cognitive behavioural therapy and education on healthy dietary and physical activity behaviour. This study examined the effect of Go4it on Health Related Quality of Life (HRQoL). METHODS: At our outpatient paediatric obesity clinic, obese adolescents (n = 122, 11-18 years) were randomly assigned to 1) Go4it, 7 sessions with an interval of 2 weeks or 2) current regular care consisting of referral to a dietician in the home care setting (controls). Linear mixed model analysis was performed to evaluate the intervention effects on HRQoL at 6 and 18-month follow-ups. HRQoL indicators included the Child Health Questionnaire, the Paediatric Quality of Life Inventory™ Version 4.0 (PedsQL™4.0), and the Body Esteem Scale (BES). RESULTS: In total, 95 adolescents (Go4it 57, controls 38) were included in the current analysis with a mean age of 14.5 ± 1.7 and mean BMI-SDS of 2.9 ± 0.5. At baseline, all participants experienced lower levels of physical and psychosocial well-being compared to a normal weight reference group. At the 18 month follow-up, we found small but beneficial intervention effects on all subscales of the PedsQL™4.0 and BES questionnaires. Two subscales improved significantly; i.e., physical health (between group difference 5.4; 95%CI: 0.3; 10.6), and school functioning (between group difference 7.4; 95%CI: 1.6; 13.2). CONCLUSION: Obese adolescents experienced lower HRQoL than their healthy peers. The Go4it intervention had small beneficial effects on HRQoL compared to the current regular care practices for obese adolescents. TRIAL REGISTRATION: Netherlands Trial Register: ISRCTN27626398, METC number: 05.134 (WMO, monocenter).

Resting-State Oscillatory Activity in Children Born Small for Gestational Age: An MEG Study.

Growth restriction in utero during a period that is critical for normal growth of the brain, has previously been associated with deviations in cognitive abilities and brain anatomical and functional changes. We measured magnetoencephalography (MEG) in 4- to 7-year-old children to test if children born small for gestational age (SGA) show deviations in resting-state brain oscillatory activity. Children born SGA with postnatally spontaneous catch-up growth [SGA+; six boys, seven girls; mean age 6.3 year (SD = 0.9)] and children born appropriate for gestational age [AGA; seven boys, three girls; mean age 6.0 year (SD = 1.2)] participated in a resting-state MEG study. We calculated absolute and relative power spectra and used non-parametric statistics to test for group differences. SGA+ and AGA born children showed no significant differences in absolute and relative power except for reduced absolute gamma band power in SGA children. At the time of MEG investigation, SGA+ children showed significantly lower head circumference (HC) and a trend toward lower IQ, however there was no association of HC or IQ with absolute or relative power. Except for reduced absolute gamma band power, our findings suggest normal brain activity patterns at school age in a group of children born SGA in which spontaneous catch-up growth of bodily length after birth occurred. Although previous findings suggest that being born SGA alters brain oscillatory activity early in neonatal life, we show that these neonatal alterations do not persist at early school age when spontaneous postnatal catch-up growth occurs after birth.

Sex differences in verbal fluency during adolescence: a functional magnetic resonance imaging study in gender dysphoric and control boys and girls.

INTRODUCTION: In the literature, verbal fluency (VF) is generally described as a female-favoring task. Although it is conceivable that this sex difference only evolves during adolescence or adulthood under influence of sex steroids, this has never been investigated in young adolescents. AIM: First, to assess sex differences in VF performance and regional brain activation in adolescents. Second, to determine if untreated transsexual adolescents differ from their sex of birth with regard to VF performance and regional brain activation. METHOD: Twenty-five boys, 26 girls, 8 Male-to-Female transsexual adolescents (MtFs), and 14 Female-to-Male transsexual adolescents (FtMs) were tested in a cross-sectional study, while performing a phonetic and semantic VF task within an MRI scanner. MAIN OUTCOME MEASURES: Functional MRI response during VF task. RESULTS: Boys and girls produced similar amounts of words, but the group MtFs produced significantly more words in the phonetic condition compared to control boys, girls, and FtMs. During the semantic condition, no differences were found. With regard to brain activity, control boys showed more activation in the right Rolandic operculum, a small area adjacent to Broca's area, compared to girls. No significant differences in brain activity were found comparing transsexual adolescents, although sub-threshold activation was found in the right Rolandic operculum indicating a trendwise increase in activation from control girls to FtMs to MtFs to control boys. CONCLUSIONS: The better performance of MtFs is consistent with our expectation that MtFs perform better on female-favoring tasks. Moreover, they produced more words than girls and FtMs. Even though a trendwise linear increase in brain activity between the four groups only approached significance, it may indicate differences in individuals with gender identity disorder compared to their birth sex. Although our findings should thus be interpreted with caution, they suggest a biological basis for both transgender groups performing in-between the two sexes.

Heritability of dietary food intake patterns.

The quality and quantity of food intake affect body weight, but little is known about the genetics of such human dietary intake patterns in relation to the genetics of BMI. We aimed to estimate the heritability of dietary intake patterns and genetic correlation with BMI in participants of the Erasmus Rucphen Family study. The study included 1,690 individuals (42 % men; age range, 19-92), of whom 41.4 % were overweight and 15.9 % were obese. Self-report questionnaires were used to assess the number of days (0-7) on which participants consumed vegetables, fruit, fruit juice, fish, unhealthy snacks, fastfood, and soft drinks. Principal component analysis was applied to examine the correlations between the questionnaire items and to generate dietary intake pattern scores. Heritability and the shared genetic and shared non-genetic (environmental) correlations were estimated using the family structure of the cohort. Principal component analysis suggested that the questionnaire items could be grouped in a healthy and unhealthy dietary intake pattern, explaining 22 and 18 % of the phenotypic variance, respectively. The dietary intake patterns had a heritability of 0.32 for the healthy and 0.27 for the unhealthy pattern. Genetic correlations between the dietary intake patterns and BMI were not significant, but we found a significant environmental correlation between the unhealthy dietary intake pattern and BMI. Specific dietary intake patterns are associated with the risk of obesity and are heritable traits. The genetic factors that determine specific dietary intake patterns do not significantly overlap with the genetic factors that determine BMI.

Growing trees in child brains: graph theoretical analysis of electroencephalography-derived minimum spanning tree in 5- and 7-year-old children reflects brain maturation.

The child brain is a small-world network, which is hypothesized to change toward more ordered configurations with development. In graph theoretical studies, comparing network topologies under different conditions remains a critical point. Constructing a minimum spanning tree (MST) might present a solution, since it does not require setting a threshold and uses a fixed number of nodes and edges. In this study, the MST method is introduced to examine developmental changes in functional brain network topology in young children. Resting-state electroencephalography was recorded from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) weighted matrices were calculated in three different frequency bands from which MSTs were constructed, which represent constructs of the most important routes for information flow in a network. From these trees, several parameters were calculated to characterize developmental change in network organization. The MST diameter and eccentricity significantly increased, while the leaf number and hierarchy significantly decreased in the alpha band with development. Boys showed significant higher leaf number, betweenness, degree and hierarchy and significant lower SL, diameter, and eccentricity than girls in the theta band. The developmental changes indicate a shift toward more decentralized line-like trees, which supports the previously hypothesized increase toward regularity of brain networks with development. Additionally, girls showed more line-like decentralized configurations, which is consistent with the view that girls are ahead of boys in brain development. MST provides an elegant method sensitive to capture subtle developmental changes in network organization without the bias of network comparison.

Salivary testosterone in female-to-male transgender adolescents during treatment with intra-muscular injectable testosterone esters.

INTRODUCTION: In our hospital, female-to-male (FtM) transgender adolescents from the age of 16 are treated with two- or four-weekly intra-muscular injections of testosterone-esters. Some patients treated with four-weekly injections have complaints of fatigue and experience mood swings towards the end of the inter-injection period, which calls for an evaluation of the time-course of testosterone levels between injections. Evaluation of salivary testosterone is a practical approach for sequential measurements. Since only ∼2% of total serum testosterone is present in saliva, a sensitive assay is necessary. The objective was to develop an isotope dilution-liquid chromatography-tandem mass spectrometry method (ID-LC-MS/MS) for salivary testosterone measurements and to evaluate the testosterone profiles after testosterone-ester mixture injections in FtM-adolescents. EXPERIMENTAL: FtM treated with 125 mg/2 weeks or with 250 mg/4 weeks depots of testosterone-ester mixture collected saliva at different time intervals. Salivary testosterone was measured by a thoroughly validated ID-LC-MS/MS assay. RESULTS: An ID-LC-MS/MS method for measuring salivary testosterone was developed with adequate accuracy and specificity. The reference range was established at 135-400 pmol/L. Testosterone levels peaked supra-physiologically immediately post-injection, and decreased to levels within the male reference range after nine days in all patients. 250 mg/4 weeks depots resulted in values below the reference range at the end of the 4 weeks. DISCUSSION: The development of an adequate ID-LC-MS/MS method for measuring salivary testosterone allowed us to investigate the testosterone profile in FtM-adolescents after testosterone-esters mixture injections. These injections lead to extreme concentrations which may affect the wellbeing of the patients.

[Obesity caused by melanocortin-4 receptor mutations]. / Obesitas door melanocortine-4-receptormutaties.

Obesity is usually the result of a combination of genetic and lifestyle factors. In monogenic obesity, overweight is caused by a single gene mutation. The most frequent form of monogenic obesity is caused by mutations in the gene that codes for the melanocortin-4 receptor (MC4R gene). Approximately 2% of Dutch children with obesity have a mutation in the MC4R gene. Children with homozygous and 'compound' heterozygous MC4R mutations have a phenotype distinguished by extreme overweight at an early age and hyperphagia. Children with heterozygous MC4R mutations have a more subtle phenotype and are difficult to distinguish clinically from obese children without this mutation. MC4R mutations can be identified by DNA diagnostics.- Drug treatment is not yet available for this condition.

Resting-state networks in awake five- to eight-year old children.

During the first 6-7 years of life children undergo a period of major neurocognitive development. Higher-order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal-directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting-state functional connectivity MRI in 5- to 8-year-old children in an awake state to identify and characterize resting-state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher-order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered.

Self-reported screen time and cardiometabolic risk in obese Dutch adolescents.

BACKGROUND: It is not clear whether the association between sedentary time and cardiometabolic risk exists among obese adolescents. We examined the association between screen time (TV and computer time) and cardiometabolic risk in obese Dutch adolescents. METHODS AND FINDINGS: For the current cross-sectional study, baseline data of 125 Dutch overweight and obese adolescents (12-18 years) participating in the Go4it study were included. Self-reported screen time (Activity Questionnaire for Adolescents and Adults) and clustered and individual cardiometabolic risk (i.e. body composition, systolic and diastolic blood pressure, low-density (LDL-C), high-density (HDL-C) and total cholesterol (TC), triglycerides, glucose and insulin) were assessed in all participants. Multiple linear regression analyses were used to assess the association between screen time and cardiometabolic risk, adjusting for age, gender, pubertal stage, ethnicity and moderate-to-vigorous physical activity. We found no significant relationship between self-reported total screen time and clustered cardiometabolic risk or individual risk factors in overweight and obese adolescents. Unexpectedly, self-reported computer time, but not TV time, was slightly but significantly inversely associated with TC (B = -0.002; CI = [-0.003;-0.000]) and LDL-C (B = -0.002; CI = [-0.001;0.000]). CONCLUSIONS: In obese adolescents we could not confirm the hypothesised positive association between screen time and cardiometabolic risk. Future studies should consider computer use as a separate class of screen behaviour, thereby also discriminating between active video gaming and other computer activities.

Sibling sex ratio and birth order in early-onset gender dysphoric adolescents.

Several sibship-related variables have been studied extensively in sexual orientation research, especially in men. Sibling sex ratio refers to the ratio of brothers to sisters in the aggregate sibships of a group of probands. Birth order refers to the probands' position (e.g., first-born, middle-born, last-born) within their sibships. Fraternal birth order refers to their position among male siblings only. Such research was extended in this study to a large group of early-onset gender dysphoric adolescents. The probands comprised 94 male-to-female and 95 female-to-male gender dysphoric adolescents. The overwhelming majority of these were homosexual or probably prehomosexual. The control group consisted of 875 boys and 914 girls from the TRAILS study. The sibling sex ratio of the gender dysphoric boys was very high (241 brothers per 100 sisters) compared with the expected ratio (106:100). The excess of brothers was more extreme among the probands' older siblings (300:100) than among their younger siblings (195:100). Between-groups comparisons showed that the gender dysphoric boys had significantly more older brothers, and significantly fewer older sisters and younger sisters, than did the control boys. In contrast, the only notable finding for the female groups was that the gender dysphoric girls had significantly fewer total siblings than did the control girls. The results for the male probands were consistent with prior speculations that a high fraternal birth order (i.e., an excess of older brothers) is found in all homosexual male groups, but an elevated sibling sex ratio (usually caused by an additional, smaller excess of younger brothers) is characteristic of gender dysphoric homosexual males. The mechanisms underlying these phenomena remain unknown.

Global and regional differences in brain anatomy of young children born small for gestational age.

In children who are born small for gestational age (SGA), an adverse intrauterine environment has led to underdevelopment of both the body and the brain. The delay in body growth is (partially) restored during the first two years in a majority of these children. In addition to a negative influence on these physical parameters, decreased levels of intelligence and cognitive impairments have been described in children born SGA. In this study, we used magnetic resonance imaging to examine brain anatomy in 4- to 7-year-old SGA children with and without complete bodily catch-up growth and compared them to healthy children born appropriate for gestational age. Our findings demonstrate that these children strongly differ on brain organisation when compared with healthy controls relating to both global and regional anatomical differences. Children born SGA displayed reduced cerebral and cerebellar grey and white matter volumes, smaller volumes of subcortical structures and reduced cortical surface area. Regional differences in prefrontal cortical thickness suggest a different development of the cerebral cortex. SGA children with bodily catch-up growth constitute an intermediate between those children without catch-up growth and healthy controls. Therefore, bodily catch-up growth in children born SGA does not implicate full catch-up growth of the brain.