References 1.b: Brains of transsexuals are in-between male and female

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria


  • Puberty suppression does not have an effect on ToL performance

  • Adolescent boys and girls show sex differences in ToL-load related brain activations

  • GnRHa treated participants with GD show sex differences similar to the control groups

  • For the untreated participants with GD no significant sex differences were found

  • Pubertal hormones induced sex-atypical brain activations in adolescents with GD

Abstract: Adolescents with Gender Dysphoria (GD) may be treated with Gonadotropin Releasing Hormone analogues (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n = 8) with untreated MFs (n = 10) or when comparing GnRHa treated female to-males (suppressed FMs, n = 12) with untreated FMs (n = 10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region- of-interest (ROI) analyses showed significantly greater activation in control boys (n = 21) than control girls (n = 24) during high task load ToL items in the bilateral precuneus and a trend (p < 0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that 1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

Author/-s:       Annemieke S. Staphorsius; Baudewijntje P.C. Kreukels; Peggy T. Cohen-Kettenis; Dick J. Veltman; Sarah M. Burke; Sebastian E.E. Schagen; Femke M. Wouters; Henriëtte A. Delemarre-van de Waal; Julie Bakker

Publication:     Psychoneuroendocrinology, 2015

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Hypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescents

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.

Author/-s:       Sarah M. Burke; Peggy T. Cohen-Kettenis; D. J. Veltman; D. T. Klink; J. Bakker

Publication:     Frontiers in Endocrinology, 2014

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White Matter Microstructure in Transsexuals and Controls Investigated by Diffusion Tensor Imaging

Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.

Author/-s:       Georg S. Kranz;  Andreas Hahn; Ulrike Kaufmann; Martin Küblböck; Allan Hummer; Sebastian Ganger; Rene Seiger; Dietmar Winkler; Dick F. Swaab; Christian Windischberger, Siegfried Kasper; Rupert Lanzenberger

Publication:     The Journal of Neuroscience, 2014

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This study was reported in some media articles: and

The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study.

Background: Diffusion tensor imaging (DTI) has been shown to be sensitive in detecting white matter differences between sexes. Before cross-sex hormone treatment female to male transsexuals (FtM) differ from females but not from males in several brain fibers. The purpose of this paper is to investigate whether white matter patterns in male to female (MtF) transsexuals before commencing cross-sex hormone treatment are also more similar to those of their biological sex or whether they are more similar to those of their gender identity.

Method: DTI was performed in 18 MtF transsexuals and 19 male and 19 female controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics.

Results: MtF transsexuals differed from both male and female controls bilaterally in the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract.

Conclusions: Our results show that the white matter microstructure pattern in untreated MtF transsexuals falls halfway between the pattern of male and female controls. The nature of these differences suggests that some fasciculi do not complete the masculinization process in MtF transsexuals during brain development.

Author/-s:       Giuseppina Rametti; Beatriz Carrillo; Esther Gómez-Gil; Carme Junque; Leire Zubiarre-Elorza; Santiago Segovia; Ángel Gomez; Antonio Guillamon

Publication:     Journal of psychiatric research, 2011

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Cognitive ability and cerebral lateralisation in transsexuals

It is still unclear to what extent cross-gender identity is due to pre- and perinatal organising effects of sex hormones on the brain. Empirical evidence for a relationship between prenatal hormonal influences and certain aspects of gender typical (cognitive) functioning comes from pre- and postpubertal clinical samples, such as women suffering from congenital adrenal hyperplasia and studies in normal children. In order to further investigate the hypothesis that cross-gender identity is influenced by prenatal exposure to (atypical) sex steroid levels we conducted a study with early onset, adult, male-to-female and female-to-male transsexuals, who were not yet hormonally treated, and nontranssexual adult female and male controls. The aim of the study was to find out whether early onset transsexuals performed in congruence with their biological sex or their gender identity. The results on different tests show that gender differences were pronounced, and that the two transsexual groups occupied a position in between these two groups, thus showing a pattern of performance away from their biological sex. The findings provide evidence that organisational hormonal influences may have an effect on the development of cross-gender identity.

Author-/s:       Peggy T. Cohen-Kettenis; Stephanie H. M. van Goozen; Cees D. Doorn; Louis J. G. Gooren

Publication:     Psychoneuroendocrinology, 1998

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