Developmental effects of androgens in the human brain

Abstract

Neuroendocrine theories of brain development posit that androgens play a crucial role in sex-specific cortical growth, although little is known about the differential effects of testosterone and dehydroepiandrosterone (DHEA) on cortico-limbic development and cognition during adolescence. In this context, the National Institutes of Health Study of Normal Brain Development, a longitudinal study of typically developing children and adolescents aged 4-24 years (n=433), offers a unique opportunity to examine the developmental effects of androgens on cortico-limbic maturation and cognition. Using data from this sample, our group found that higher testosterone levels were associated with left-sided decreases in cortical thickness (CTh) in post-pubertal boys, particularly in the prefrontal cortex, compared to right-sided increases in CTh in somatosensory areas in pre-pubertal girls. Prefrontal-amygdala and prefrontal-hippocampal structural covariance (considered to reflect structural connectivity) also varied according to testosterone levels, with the testosterone-related brain phenotype predicting higher aggression levels and lower executive function, particularly in boys. By contrast, DHEA was associated with a pre-pubertal increase in CTh of several regions involved in cognitive control in both boys and girls. Covariance within several cortico-amygdalar structural networks also varied as a function of DHEA levels, with the DHEA-related brain phenotype predicting improvements in visual attention in both boys and girls. DHEA-related cortico-hippocampal structural covariance, on the other hand, predicted higher scores on a test of working memory. Interestingly, there were significant interactions between testosterone and DHEA, such that DHEA tended to mitigate the anti-proliferative effects of testosterone on brain structure. In sum, testosterone-related effects on the developing brain may lead to detrimental effects on cortical functions (ie, higher aggression and lower executive function), whereas DHEA-related effects may optimise cortical functions (ie, better attention and working memory), perhaps by decreasing the influence of amygdalar and hippocampal afferents on cortical functions.

Cerebral sex dimorphism and sexual orientation

“…Testosterone affects also Cth (leading to thinning of the parietal and thickening of the superior temporal lobe cortex, and decreased frontal lobe grey matter volume in boys, (Bramen et al, ; Nguyen et al, ; Witte, Savli, Holik, Kasper, & Lanzenberger, ), and a thickening of the cuneus, lingual and pericalcarine cortex in trans men (Zubiaurre‐Elorza et al, ), and the detected differences in Cth between HoM and HeM, could reflect a regional hypoandrogenization in HoM. Altered androgenization in regard to both FA and Cth could be result of altered fetal testosterone exposure (Hines, ), altered circulating testosterone later in life (Bramen et al, ; Nguyen, ; Nguyen et al, ; Nopoulos, Flaum, O'leary, & Andreasen, ; Savic & Arver, ), or changes in androgen receptor binding properties, which may occur, for example, as an effect of different CAG repeats (Paus et al, ; Raznahan et al, ).…”

New perspectives for the action of steroids in the brain

“…10 The role of testosterone and the regulation of the enzyme, aromatase, is the theme of the next 3 papers. [11][12][13] The expression of aromatase (which converts testosterone into oestradiol) is regulated by several factors, including sex hormones, genes and neurosteroids; therefore, these actors may impact on the organisational effects of steroids during development. 11 However, testosterone is not only the source for the local synthesis of oestradiol, but also it might regulate the development of sexually differentiated circuits, as revealed by studies in mice with mutations in the androgen receptor.…”

“…12 Furthermore, androgens (eg, testosterone and dehydroepiandrosterone) play a crucial role in sex-specific cortical growth during development and adolescence. 13 In addition, neurosteroids (ie, brain-derived steroids, such as allopregnanolone) are involved in the regulation of brain development.…”

“…The role of testosterone and the regulation of the enzyme, aromatase, is the theme of the next 3 papers . The expression of aromatase (which converts testosterone into oestradiol) is regulated by several factors, including sex hormones, genes and neurosteroids; therefore, these actors may impact on the organisational effects of steroids during development .…”

“…However, testosterone is not only the source for the local synthesis of oestradiol, but also it might regulate the development of sexually differentiated circuits, as revealed by studies in mice with mutations in the androgen receptor . Furthermore, androgens (eg, testosterone and dehydroepiandrosterone) play a crucial role in sex‐specific cortical growth during development and adolescence …”