Fetal testosterone influences sexually dimorphic gray matter in the human brain

Abstract

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

Figure 1.

FT correlations with local GM volume. A, Areas where FT predicts local gray matter volume. Red/orange voxels denote positive correlations; blue voxels denote negative correlations. B, Areas of sexual dimorphism in local GM volume. Red/orange voxels denote a Male > Female pattern; blue voxels denote a Female > Male pattern.

Figure 2.

Overlap of FT–GM correlations and sexual dimorphism. A, Conjunction analysis overlap between sexual dimorphism and FT correlation in PT/PO, plOFC, and RTPJ/pSTS. Red voxels show overlap from the conjunction of FT positive correlation and Male > Female; blue voxels show overlap from the conjunction of FT negative correlation and Female > Male. B, Scatterplot showing the partial correlation between FT and GM volume within sexually dimorphic voxels in right PT/PO. Adjusted predictor and outcome values are plotted on the x and y axes. C, Scatterplot showing the partial correlation between FT and GM volume within sexually dimorphic voxels in RTPJ/pSTS. Adjusted predictor and outcome values are plotted on the x and y axes. D, Scatterplot showing the partial correlation between FT and GM volume within sexually dimorphic voxels in right plOFC. Adjusted predictor and outcome values are plotted on the x and y axes.