Role of testosterone and Y chromosome genes for the masculinization of the human brain

Abstract

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls.

Methods: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI.

Results: Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern.

Conclusion: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: MRI; Y-chromosome; disorders of sexual differentiation; gender.

Figure 1

Group difference in Cth. The contrasts were calculated at P < 0.05, FWE corrected for multiple comparisons (Monte Carlo permutation). The projection of cerebral hemispheres (MR images of the FreeSurfer atlas) is standardized. Scale is logarithmic and shows –log10(P), with cool colors indicating negative contrast (lower values in male controls, women with CAIS), and warm colors positive contrast.

Figure 2

Group difference in FA. The differences are illustrated in red–yellow and superimposed on the group skeleton (green). These clusters were calculated at P < 0.05, FWE corrected for multiple comparisons. Both female groups differed from male controls. The difference in forceps major and ACC was significant only when contrasting data between male and female controls, however, a similar cluster appeared also when contrasting FA from male controls and women with CAIS (males‐CAIS women), but only when changing the threshold level to P < 0.1, FWE corrected). At P < 0.1, FWE corrected there was also a CC cluster, indicated in light blus, when contrasting female controls‐women with CAIS. MNI co‐ordinates are indicated for the two sets of images.

Figure 3

Group difference, in rs‐fMRI, default mode network (DMN). Significant group differences in resting state functional connections within the default mode network (indicated in yellow), which was used as a mask, are shown. Differences between female and male controls in the precuneus are indicated in red–yellow; the corresponding cluster from the CAIS women–male controls contrast is indicated in green. Clusters calculated at P < 0.05, FWE corrected. MNI co‐ordinates for the two clusters are indicated.