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

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Abstract

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.

Introduction

Transsexualism is an extreme form of gender identity disorder (American Psychiatric Association, 2000). Male to female (MtF) transsexuals are characterized by persistent cross-gender identification, discomfort with their assigned gender, cross-dressing and a search for hormonal and surgical sex reassignment to the desired anatomical sex to become females. The etiology of transsexualism is unknown but biological variables could play a role in its development (Cohen-Kettenis and Gooren, 1999, Gooren, 2006, Swaab, 2004).

Postmortem anatomical studies have shown that some subcortical structures are feminized in MtF transsexuals. The volume and the number of neurons of the central part of the bed nucleus of the stria terminalis (BSTc) and the third interstitial nucleus of the anterior hypothalamus (INAH3), which present sex differences in control subjects, are feminized in MtF transsexuals (Garcia-Falgueras and Swaab, 2008, Kruijver et al., 2000, Zhou et al., 1995). These studies all suggest that the feminization of the BSTc and the INAH3 in MtF transsexuals is related to neither their sexual orientation nor their cross-hormonal treatment.

Only a few structural and functional MRI studies focus on MtF transsexuals. Luders et al. (2009) found that, before cross-sex hormone administration, the regional structure of the gray matter in MtF transsexuals was more similar to the pattern found in males than in females. Nevertheless, the transsexuals did show a significantly larger volume of gray matter in the right putamen than did control males.

MRI functional studies of transsexuals analyze 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. Sommer et al. (2008), using a longitudinal design, found that activation during mental rotation did not increase during cross-sex hormone treatments, probably because of their small sample size. However, in a sample of treated and untreated MtF transsexuals and control males, it was reported that both transsexual groups had increased activation in the temporo-occipital regions and decreased activation in the left parietal lobe, suggesting a priori differences between control males and MtF transsexuals (Schöning et al., 2010). In addition, comparing chronically hormone treated MtF and FtM 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).

There are two additional functional neuroimaging works that addressed the cerebral patterns of MtF transsexuals. Gizewski et al. (2009) studied the cerebral activation produced by visual erotic stimuli in MtF transsexuals before treatment and found an activation pattern in MtF transsexuals similar to that observed in females. They suggested that MtF transsexuals show a tendency toward female-like cerebral processing. Moreover, Berglund et al. (2008), using positron emission tomography (PET), studied brain activation in MtF transsexuals when smelling 4, 16-androstendien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST). These steroids activate the hypothalamus in a sex-differentiated manner (Savic et al., 2001). Smelling AND and EST, MtF transsexuals showed a pattern of activation that was different from their biological sex and was situated in an intermediate position with predominantly female-like features (Berglund et al., 2008).

There are two structural MRI studies focused on white matter in transsexuals. The earliest (Emory et al., 1991) found no differences for the whole corpus callosum (CC) or the splenium region between transsexuals and controls. A more recent work, measuring CC shape, concluded that the pattern of CC shape in transsexuals is closer to that in individuals with the same gender identity than to that in individuals with the same biological sex (Yokota et al., 2005).

Diffusion Tensor Imaging (DTI) is the most suitable technique for detecting subtle changes in the white matter of patients with psychiatric disorders (Nucifora et al., 2007). DTI has been used to investigate sex differences in adults (Huster et al., 2009, Westerhausen et al., 2003) and in developmental studies (Schmithorst et al., 2008). Recently, we used DTI to investigate whether white matter patterns of female to male (FtM) transsexuals, who had not begun cross-sex hormone treatment, were more similar to that of their biological sex or to that of their gender identity (Rametti et al., in press). We found sex differences in the white matter microstructure of some brain fasciculi. Compared to control females, FtM transsexuals showed higher fractional anisotropy (FA) values in the anterior and posterior parts of the right superior longitudinal fasciculus and the forceps minor. However, in the corticospinal tract, FA values in FtM transsexuals are significantly less than in males and significantly greater than in females. Thus, we suggested that, for some fasciculi involved in higher cognitive functions, the white matter microstructure pattern in FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than to those who share their biological sex (females).

Mammalian brain sex differences, even in humans, occur in complex networks (García-Falgueras et al., 2006, Segovia and Guillamón, 1993). If FtM transsexuals show a tendency to have masculinized FA values in some brain fasciculi it could be expected that the opposite would be true for MtF transsexuals. Therefore, the purpose of the present study was to test if the pattern of the white matter microstructure in MtF transsexuals shows a trend toward feminization. We measured FA, which is related to the ordered arrangement of myelinated fibers (Beaulieu, 2002), as an indicator of white matter coherence and axonal organization (Lebel et al., 2008). To the best of our knowledge there are no previous studies in the literature describing white matter microstructure in MtF transsexuals.

Section snippets

Subjects

We recruited 18 untreated MtF transsexuals, 19 female and 19 male controls for this study. Two mental health professionals from the Gender Identity Unit (GIU) at the Hospital Clínic of Barcelona performed several semi-structured clinical interviews (Bobes et al., 1997, Gómez-Gil et al., 2009a). The estimated prevalence rate of transsexualism in Catalonia (Spain) 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., 2009b).

Psychological

Results

As expected, male controls have greater gray and white matter as well as CSF volumes than female controls. MtF have similar global volumes to male controls and these volumes differed significantly from those of the females (Table 2).

The whole TBSS analysis showed that control males have significantly higher FA values than control females in the left and the right superior longitudinal fasciculus, in the right inferior front-occipital fasciculus, the left cingulum, the forceps minor, and the

General discussion

From the analysis of FA, which indicates white matter coherence and axonal organization (Lebel et al., 2008), the main result of our study is that MtF transsexuals differ from both male and female controls in almost all the fascicles that showed sex differences. Interestingly the FA values of these fasciculi in MtF transsexuals fall halfway between those of the fasciculi in the male and female controls and are significantly different from either of the control FA values.

MtF transsexuals

Conclusion

In conclusion, our results show that the white matter microstructure pattern in untreated MtF transsexuals is intermediate between male and female controls. The direction of the differences suggests that some fasciculi do not complete the masculinization process during brain development before the individual seeks treatments.

Role of funding source

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

Contributors

None.

Conflict of interest

None.

Acknowledgments

We are grateful to the patients and control subjects that voluntarily participated 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 Rosa Sánchez and C F Warren for their editorial help.

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