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 trained 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. To date we have studied over 90 prepubertal children who were clearly identified as pre-gonadarchal by clinician-performed pubertal staging (PS) and bone age at study entry. These children have been studied longitudinally across several pubertal stages and other key developmental milestones. Given the variability in the timing of these milestones within individual children, we have retrospectively identified the onset of each milestone and we will analyze the neuroimaging data prior to and after these events. These milestones include several physiologically important events that occur during puberty/adolescence and could impact brain development as follows: first, the onset of gonadarche, which can be defined by the transition from PS1 to PS2 or the inflection point for the expansion of MRI-measured testicular and ovarian volumes (a sentinel event indicating the initial activation of the GnRH pulse generator and gonadotropin secretion at the beginning of gonadarche) or more specific markers as they emerge in the literature (e.g., declining plasma levels of makorin); second, adrenarche, which can be defined by the transition from PS1 to PS2 pubic hair or biochemically by an initial rise in circulating adrenal androgens (i.e., plasma levels of DHEA sulfate (DHEAS) > 40 g/dL); third, menarche in girls defined by the first episode of menstrual bleeding and later accompanied by cyclic ovarian steroid secretion and ovulatory cycles in some but not all girls; and fourth, the growth spurt, which can be defined by the maximum velocity of growth achieved for each child. In addition to investigating the neuroimaging data prior to and after these milestone events, we will test selected hypotheses emerging from the literature about the potential interaction of sex steroid exposure during puberty and genetic variation (e.g., BDNF, SLC6A4, GSK3, MAOA) on the developmental trajectory of brain outcomes and behaviors. Finally, using blood samples obtained in our pre-pubertal cohort at each longitudinal visit, we will examine the methylome as children transition across puberty. We will implement a two-pronged analytical approach including both hypothesis-driven and data-driven analyses. For each of our endocrine and neuroimaging outcome measures, events or trajectories will be analyzed both independently and in an integrated manner (e.g., using principal component analysis) depending on the specific questions being investigated. Our hypothesis-driven approaches will be based on the extant literature and will include assessments of the impact of both discrete milestone attainment (as described above) and longitudinal trajectories of endocrine/metabolic measures on our neuroimaging modalities. Finally, our data-driven approaches will include techniques such as machine learning, multivariate statistical modelling, latent growth modelling, and methods of dimensional reduction to explore linked patterns of covariation between brain development and the physiologic events of puberty. Adrenarche, an early stage of the pubertal transition, is marked by increases in neuroactive adrenal androgens, including dehydroepiandrosterone sulfate (DHEAS). However, the specific impact of DHEAS on neurodevelopment is difficult to disambiguate from that of gonadal hormones as both systems overlap in their maturational trajectories. We investigated the relationship between DHEAS concentrations and gray matter volume (GMV) in prepubertal children studied prior to increases in gonadal hormones (i.e., gonadarche). Fasting morning blood samples and neuroimaging data were collected on ninety-two healthy children (55 boys, age = 8.6 + 3years; 37girls, age = 8.6 + 3years) ascertained by clinician physical examination to be prepubertal. Children underwent structural T1-weighted MRI in a 3T scanner, and serum DHEAS concentrations were measured with liquid chromatography-tandem mass-spectrometry. A whole-brain, voxel-wise multivariate-model analysis (AFNI) was used to examine log-transformed DHEAS effects on GMV, controlling for sex and total brain volume. Post-hoc non-parametric correlations were conducted in SPSS. We observed effects of DHEAS on GMV in the right superior frontal gyrus, anterior cingulate cortex, and right amygdala (ps<0.001). These results identify an association between serum DHEAS and GMV prior to gonadarche and support previous studies documenting associations between DHEA and cortical thickness in prepubertal children. These data also suggest that DHEA(S) may play a role in extending the window of neurodevelopmental plasticity commonly associated with gonadarche.