Male-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone

Abstract

Background: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT).

Methods: Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well.

Results: We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (p_FWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (p_FWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation.

Limitations: Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses.

Conclusion: Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.

Fig. 1

Brain activation pattern during mental rotation at session 1 in (A) control boys, (B) girls with gender dysphoria (GD) and (C) control girls. Statistical parametric maps were rendered on an SPM8 template image showing the left and right hemisphere in sagittal view. For illustrative purposes, whole brain results are displayed at an uncorrected threshold of p < 0.005.

Fig. 2

Between-group differences in brain activation in right frontal and left parietal areas during mental rotation at session 1. Red = control girls > control boys; blue = control girls > girls with gender dysphoria. Numbers indicate x axis coordinates in Montreal Neurological Institute space, displayed in sagittal view. See Table 3 for further details.

Fig. 3

Clusters of significant increases in brain activation during mental rotation for session 2 compared with session 1. Left parietal and left frontal regions are shown. Yellow = session 2 > session 1 in girls with gender dysphoria; purple = session 2 > session 1 in control boys. See Table 4 for further details.