White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study

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Abstract

Background

Some gray and white matter regions of the brain are sexually dimorphic. The best MRI technique for identifying subtle differences in white matter is diffusion tensor imaging (DTI). The purpose of this paper is to investigate whether white matter patterns in female to male (FtM) transsexuals before commencing cross-sex hormone treatment are more similar to that of their biological sex or to that of their gender identity.

Method

DTI was performed in 18 FtM transsexuals and 24 male and 19 female heterosexual controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter fibers of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics.

Results

In controls, males have significantly higher FA values than females in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract.

Conclusions

Our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females). Our results provide evidence for an inherent difference in the brain structure of FtM transsexuals.

Introduction

Gender identity disorders (GID) are characterized by persistent cross-gender identification and discomfort with the individual’s assigned gender (American Psychiatric Association, 2000). The disorders are manifested by cross-dressing and a search for hormonal and surgical sex reassignment (SR) to the desired anatomical sex. Transsexualism is an extreme form of GID. The etiology of GID is unknown but biological variables may contribute to gender identity variations (Cohen-Kettenis and Gooren, 1999, Swaab, 2004).

Structural brain differences in transsexuals have been addressed by postmortem anatomical as well as by in vivo neuroimaging studies. With respect to the former, it was shown in subcortical structures that the central nucleus of the bed nucleus of the stria terminalis (BSTc), which is important for the male sexual behavior (Claro et al., 1995), is female in size (Zhou et al., 1995) and in neuron number (Kruijver et al., 2000) in male-to-female (MtF) transsexual subjects. These structural differences between MtF transsexuals and their male and female controls were not influenced by changes in sex hormone levels in adulthood and were not related to sexual orientation (Kruijver et al., 2000, Zhou et al., 1995). Additionally, one of the interstitial nuclei of the anterior hypothalamus (INAH3) is larger in men than in women. The volume and number of neurons in the INAH3 of MtF transsexuals was similar to that of control females and this feminization was not due to estrogens treatment (Garcia-Falgueras and Swaab, 2008). The latter study included one FtM transsexual subject; the INAH3 volume and number of neurons was within the male control range (Garcia-Falgueras and Swaab, 2008).

Although brain MRI structural and functional studies may help to understand transsexualism, few studies have yet been made. The only available structural study (Luders et al., 2009) analyzed MRI data of not yet cross-sex hormone treated MtF transsexuals in order to verify whether their gray matter volumes resembled those of subjects who shared either their biological sex (males) or their gender identity (females). They reported that regional gray matter variation in untreated MtF transsexuals is more similar to the pattern found in males than in females. However, MtF transsexuals show a significantly larger volume of regional gray matter in the right putamen than do control men (Luders et al., 2009).

MRI functional studies examinated the brain while performing tasks, such as mental rotation, in which males and females consistently differ (Kimura, 1999). There are only three fMRI studies of mental rotation in transsexuals. One longitudinal study reported that activation during mental rotation did not increase during cross-sex hormone treatments (Sommer et al., 2008), probably because of the small sample size. However, in a sample of treated and untreated MtF it was found that both transsexual groups had increased activation in the temporo-occipital regions and decreased activation in the left parietal lobe, compared to control men. The authors suggested that are a priori differences between males and MtF transsexuals (Schöning et al., 2009). Also in a mental rotation task, comparing chronically treated FtM and MtF transsexuals to male and female controls, we found a parietal hypoactivation in the MtF transsexuals, but no significant differences for FtM transsexuals (Carrillo et al., 2010).

Cerebral activation due to visual erotic stimuli in MtF transsexuals before any treatment has been investigated by means of fMRI (Gizewski et al., 2009). These authors found an activation patter in MtF transsexuals that is similar to the one of females. They concluded that MtF transsexuals show a tendency of female-like cerebral processing in transsexualism.

A couple of MRI studies have focused on white matter in transsexuals. No differences for the whole corpus callosum (CC) or splenium region between transsexuals and controls were reported (Emory et al., 1991). However, using a sophisticated MRI measure of CC shape, it was concluded that the pattern of CC shape in transsexuals is closer to that in individuals whit the same gender identity than to that in individual with the same biological sex (Yokota et al., 2005).

Diffusion Tensor Imaging (DTI) is the most suitable technique to detect subtle changes in the white matter of patients with schizophrenia, depression, obsessive-compulsive disorders, autism or developmental dyslexia (Nucifora et al., 2007). DTI has been used to investigate sex differences in adults (Westerhausen et al., 2003, Huster et al., 2009) and in developmental studies (Schmithorst et al., 2008).

Almost all of the postmorten anatomical (Garcia-Falgueras and Swaab, 2008, Kruijver et al., 2000, Zhou et al., 1995) and MRI (Luders et al., 2009) studies have been focused on the gray matter of MtF transsexuals and little attention has been paid to white or gray matter in FtM transsexuals. Thus, the purpose of the present study was to test if the pattern of the white matter microstructure in FtM transsexuals was congruent with their biological sex or with their gender identity before they underwent cross-sex hormonal treatment. We measured FA as an indicator of white matter coherence and axonal organization. To the best of our knowledge there are no previous studies in the literature describing white matter microstructure in FtM transsexuals.

Section snippets

Subjects

Subjects were 18 untreated FtM transsexuals from the Gender Identity Unit (GIU) at the Hospital Clinic of Barcelona, with 24 male and 19 female controls recruited by advertisement (see Table 1). All participants were right handed.

The prevalence rate of transsexualism in Catalonia is 1:21,031 males and 1:48,096 females and the sex ratio is 2.6 (Gómez-Gil et al., 2005, Gómez-Gil et al., 2009a). Diagnostic assessment of transsexualism followed the revised fourth edition of the Diagnostic and

Results

Whole brain TBSS analysis showed that control males have significantly higher FA values than the control female group in the anterior and posterior parts of the right superior longitudinal fasciculus, forceps minor, and the corticospinal tract (Fig. 1 and Table 2). The contrast analysis testing for females being greater than males did not show any significant difference.

We performed ANOVA analyses of the FA mean values for each region that showed sexual differences. Compared to control females,

General discussion

Measuring FA, an indicator of white matter coherence and axonal organization (Lebel et al., 2008), the main result of our study is that untreated FtM transsexuals differed from control females in two associative fasciculi (superior longitudinal fasciculus and forceps minor) and in the corticospinal tract. In contrast they only differed from control males in the corticospinal tract. These findings indicates that prior to hormonal cross-sex treatment the white matter microstructure of associative

Conclusion

In conclusion, our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than to those who share their biological sex (females). Our results provide evidence for structural differences in the untreated FtM transsexual’s brain.

Contributors

None.

Conflict of interest

None.

Role of funding source

Funding for this study was provided by the Spanish Ministerio de Ciencia e Innovación (MNICIN) grant SEJ2007-65686 (Dr. Guillamon). MNICIN had no further role in any step of the present study.

Acknowledgments

We are grateful to the patients and control subjects that voluntarily participate in the study. Thanks are due to Drs. M. A. Amerigo, N. Bargalló, C. Falcón, J. Llul and S. Juanes for their help at some phases of the study and to R. Sánchez and C. Warren for their editorial help.

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