Endocrine and Neurobiologic Events Accompanying Puberty

National Institute Of Mental Health

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Abstract

This report includes work arising from the following clinical protocol: NCT01434368. A prepubertal cohort enters the study at age 8, and clinicians determine that each child meets Pubertal stage (PS) 1 criteria (i.e., no evidence of secondary sexual characteristics in breast, testes, or pubic hair), is medically well, is between the 15th and 85th percentile BMI, and has radiologic evidence of age-appropriate bone development. The absence of psychiatric illness in each child is confirmed (at each visit) by structured interview (i.e., K-SADS), and we confirm the absence of Axis I psychiatric illness in any first-degree relatives. A second cohort enters the study at 12-13 years (PS 2-3) and meets the same selection criteria as those in the prepubertal cohort. Behavioral measures include ratings of mood, social experiences within family and amongst peers, sleep, as well as measures of early life trauma Reproductive endocrine (i.e., gonadal and adrenal steroids measured by LC-MS/MS), bone age (a reflection of cumulative tissue exposure to estradiol in both boys and girls), metabolic (i.e., MRI and dual-energy X-ray absorptiometry DEXA measures of visceral fat and body composition), and physical measures (i.e., anthropomorphic indices, MRI measures of gonadal volume) are employed to fully characterize the stages, duration and tempo of pubertal development. Brain outcome measures derived via multimodal neuroimaging techniques include the following: resting-state fMRI, structural MRI, DTI, and four fMRI tasks (i.e., emotional processing, reward, impulse inhibition and working memory). These latter fMRI tasks were selected because they target neural systems reported to undergo both structural and functional transformation during adolescence and are relevant for neuropsychiatric disorders. Finally, all participants provide blood samples for genotyping, methylome measures and for the formation of cell-lines (LCLs, h-IPCs) in which functional genomics studies could be performed investigating the effects of puberty-related endocrine events on the transcriptome. This past year we have initiated a collaborative relationship with the pediatric gynecology service at the NIH CC who will employ the MRI measures of gonadal volumes to examine the effects of puberty on these measures as well as employing these measures in comparison to adolescent girls with several forms of ovarian pathology including Turners syndrome, polycystic ovaries and those with premature ovarian insufficiency. The recruitment to date is as follows: 122 children are currently enrolled or completed the study; of those 34 children who completed all visits (8 Y.O. cohort = 5 3 boys, 2 girls; (12/13 Y.O. cohort = 19 9 boys, 10 girls). Eighty-eight children are currently enrolled (8 Y.O. = 65 33 boys, 32 girls, 12/13 Y.O. = 23 9 boys, 14 girls. Additionally, a subgroup of children in whom we study the effects on brain of advanced bone age (reflecting earlier or greater tissue exposure to estradiol, we have completed single visits in 10 children (8 Y.O. cohort = 3 2 boys, 1 girl; (12/13 Y.O. Cohort = 7 4 boys, 3 girls). Finally, three adults have completed the 5-year serial measures to serve as controls for the effects of time on neuroimaging measures. Adrenarche, is the activation of the adrenal androgen secretion, a uniquely human phenomenon that plays an important role in puberty. However, the impact of adrenal androgens, including dehydroepiandrosterone sulfate (DHEAS), on neurodevelopment has been difficult to disambiguate from that of gonadal hormones. To investigate adrenarche-specific changes in prepubertal brain function, we studied typically-developing children who were carefully documented to be prepubertal as ascertained by clinicians, and thus had no puberty-related increases in gonadal hormones. In this study, we examine the impact of DHEAS on brain activations associated with inhibitory control, reward and face processing. Preliminary findings identify a potential role for adrenarche in brain development and are as follows: Inhibitory control: (84 prepubertal children, 34 girls, 50 boys), plasma DHEAS levels were positively related to left inferior frontal gyrus (LIFG) activation in both sexes (p<0.001). No correlations with age and no sex differences in LIFG activation or DHEAS were observed; Face processing: (88 prepubertal children, 37 girls, 51 boys), a significant interaction between plasma DHEAS levels and sex in the right dorsolateral prefrontal cortex (dlPFC) activation, and a significant correlation between DHEAS levels and dlPFC activation that was positive in girls, but negative in boys. Reward processing: (90 prepubertal children, 37 girls, 53 boys), during reward receipt, plasma DHEAS levels were positively correlated with left hippocampal and right ventromedial prefrontal cortex activation. During reward anticipation, activations in bilateral dorsolateral prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex, and caudate were negatively correlated with DHEAS levels. These findings in children who are otherwise at similar stages pre-puberty (i.e., pre-gonadarche) that the onset of adrenarche and adrenal androgen secretion can impact brain development in these typically-developing children. Additionally, we have preliminary data suggesting the following: 1) sex differences in developmental trajectories of DLPFC and hippocampal recruitment during spatial working memory (WM) across the pubertal transition. Future longitudinal investigations will incorporate the effects of sex hormones, as well as the role of pubertal stage and tempo, on WM-related brain development throughout this dynamic developmental period; 2) Quantitative maps of myelin water fraction (MWF) using mcDESPOT imaging identified sex- and puberty tempo-related differences in developmental trajectories of global and tract-specific MWF across puberty. Future investigations will probe pubertal timing and its impact on developmental trajectories in brain structure and neural tracts; and 3) employing arterial spin labeling (ASL) a measure of regional cerebral blood flow (rCBF), we observed a steep rCBF divergence between sexes that began during the peripubertal period, suggesting an important neurodevelopmental event. On-going analysis of hormone levels in this cohort will elucidate potential endocrinological correlates of this observation. Finally, in a companion study examining the brain developmental trajectory in children with Williams syndrome (WS) and the typically-developing children in this study, we empirically show that 7q11.23 copy-number (CNV) is significantly associated with age at menarche (AAM), as well as with pituitary gland volume. Examining prior GWAS data, we find a significant signal in the telomeric portion of the 7q11.23 locus (rs2267812) whose variation was associated with altered expression of STAG3L2 in postmortem brains, and using RNAseq, we found dose-dependent differences in expression of STAG3L2 in peripheral lymphocytes of individuals with 7q11.23 CNVs. Collectively, these data indicate that 7q11.23 plays a meaningful role in pubertal onset and suggest that the pituitary development and STAG3L2 may be important elements of this role.