Interactive Effects of Dehydroepiandrosterone and Testosterone on Cortical Thickness during Early Brain Development

Abstract

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key endocrine event associated with prepubertal increases in the adrenal production of androgens, most significantly dehydroepiandrosterone (DHEA) and to a certain degree testosterone. Adrenarche also coincides with the emergence of the prosocial and neurobehavioral skills of middle childhood and may therefore represent a human-specific stage of development. Both DHEA and testosterone have been reported in animal and in vitro studies to enhance neuronal survival and programmed cell death depending on the timing, dose, and hormonal context involved, and to potentially compete for the same signaling pathways. Yet no extant brain-hormone studies have examined the interaction between DHEA-and testosterone-related cortical maturation in humans. Here, we used linear mixed models to examine changes in cortical thickness associated with salivary DHEA and testosterone levels in a longitudinal sample of developmentally healthy children and adolescents 4 -22 years old. DHEA levels were associated with increases in cortical thickness of the left dorsolateral prefrontal cortex, right temporoparietal junction, right premotor and right entorhinal cortex between the ages of 4 -13 years, a period marked by the androgenic changes of adrenarche. There was also an interaction between DHEA and testosterone on cortical thickness of the right cingulate cortex and occipital pole that was most significant in prepubertal subjects. DHEA and testosterone appear to interact and modulate the complex process of cortical maturation during middle childhood, consistent with evidence at the molecular level of fast/nongenomic and slow/genomic or conversion-based mechanisms underlying androgen-related brain development.

Dehydroepiandrosterone impacts working memory by shaping cortico-hippocampal structural covariance during development

“…Existing studies of human brain development support the notion that DHEA may be involved in preserving cortical plasticity in brain networks involved in cognitive control, such as the left dorsolateral prefrontal cortex, right temporoparietal junction, right premotor and right entorhinal cortex, particularly in children age 4–13 years old (Nguyen et al, 2013b). Reports of DHEA administration in adults also outline beneficial effects on cognition overall, with a certain specificity for working memory and attention (Alhaj et al, 2006; Davis et al, 2008; de Menezes et al, 2016; do Vale et al, 2014).…”

“…Though levels of DHEA do not tend to show significant sex differences, some, though not all, studies suggest that sex could moderate the impact of adrenarche on brain function and mental health vulnerability, and the physical changes of adrenarche tend to occur at an earlier age in girls compared to boys (Byrne et al, 2017). DHEA may stimulate neurogenesis and protect against neuronal injury by opposing the neurotoxic effects of glucocorticoids in hippocampal as well as cortical structures (Jin et al, 2016; Karishma and Herbert, 2002; Kimonides et al, 1998; Nguyen et al, 2013b). These neurotoxic effects of glucocorticoids, which can affect both the cortex and hippocampus, may be especially detrimental during childhood and adolescence, as the brain experiences an accelerated increase in metabolic activity and cerebral perfusion throughout the pubertal maturation process (Campbell, 2011; Satterthwaite et al, 2014).…”

“…More specifically, hippocampal-to-cortical afferents may be instrumental in the process of spatial encoding and spatial working memory (Spellman et al, 2015). In turn, DHEA may be involved in bolstering both cortical and hippocampal plasticity (Jin et al, 2016; Karishma and Herbert, 2002; Kimonides et al, 1998; Nguyen et al, 2013b), and DHEA levels or administration have been linked to improved attention and working memory in some, though not all, studies (do Vale et al, 2014; Nguyen et al, 2016; Ritsner et al, 2006; Strous et al, 2001; Wolf et al, 1998). Taken together, the current literature thus suggests that DHEA could significantly impact working memory during childhood and adolescence through an alteration in cortico-hippocampal networks.…”

“…Third, we tested whether the relationship between DHEA and working memory was mediated by cortico-hippocampal structural covariance. Finally, because DHEA previously showed age-related associations with cortical thickness (Nguyen et al, 2013b), and because sex may moderate both the impact of DHEA on brain structure and working memory (Byrne et al, 2017), we tested for age and sex interaction effects in all of the above relationships. We hypothesized that DHEA levels would be associated with cortico-hippocampal structural covariance, particularly in regions involved in cognitive control.…”

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

“…9 In humans, also, DHEA appears to shape amygdala-dependent cortical plasticity as measured by functional magnetic resonance imaging studies. 10,11 DHEA supplementation in clinical and epidemiological studies As described elegantly by Labrie and Labrie, while synthesis of androgens and estrogens have an evolutionary history that is several hundred million years old, the advent of high levels of circulating DHEAS is a recent evolutionary event, originating primarily in primates and a very few other mammalian species about 20 million years ago. 12 DHEAS can circulate in high concentrations systemically because it is safe, essentially inactive as a steroid, and yet can be rapidly transformed into DHEA and then into steroids on an as needed basis in various peripheral tissues.…”