Regional gray matter variation in male-to-female transsexualism
Introduction
Individuals who identify as transsexual report a history of persistent discomfort with the sex they were assigned at birth and a strong identification with the opposite sex. Many describe significant symptoms of psychological distress (Sánchez and Vilain, 2009) and take steps to alter features of their bodies (e.g., through the use of sex hormones and plastic surgery) to make them congruent with their sense of gender. While no formal epidemiological study has been conducted in the United States, reports from European and Asian countries estimate that the prevalence of transsexualism ranges from 1:100,000 to 1:2900 (DeCuypere et al., 2007).
Despite increased public awareness of transsexualism, our scientific understanding of the development of gender identity is limited. Both environmental events (Eagly and Wood, 1999, Wood and Eagly, 2002) and innate differences (Breedlove, 1994, Dorner, 1985, Gooren, 2006) have been implicated as influencing this fundamental human characteristic. Regarding transsexualism, it has been suggested that sexual differentiation of the brain during embryonic development deviates from the sexual differentiation of the rest of the body (Zhou et al., 1995). This hypothesis implies that neuroanatomy plays a critical role in determining gender identity. Thus, the study of the underlying correlates of transsexualism may help to further identify the mechanisms that contribute to the development of gender identity.
To explore this hypothesis, several studies examined brain structures in male-to-female (MTF) transsexuals. One early in vivo study did not detect any associations between transsexualism and the anatomy of the corpus callosum (Emory et al., 1991). However, two subsequent post mortem brain analyses revealed that MTF transsexuals had a female-like central subdivision of the bed nucleus of the stria terminalis (BSTc) with respect to its size (Zhou et al., 1995) and number of neurons (Kruijver et al., 2000). Another post mortem study published recently reported female-like volumes and neuronal densities of the interstitial nucleus of the anterior hypothalamus (INAH3) in MTF transsexuals (Garcia-Falgueras and Swaab, 2008). These three post mortem studies seem to support the hypothesis that brain anatomy is associated with transsexualism. Yet, the generalization of these findings is limited by the inherent pitfalls of post mortem studies, the relatively small number of MTF transsexuals examined (n1 = 6; n2 = 6; n3 = 11), as well as the subjects' long-term treatment with estrogen. Granted, some argue that estrogen treatment does not alter certain brain structures (Garcia-Falgueras and Swaab, 2008). Nevertheless, other studies have shown that treatment with anti-androgen and estrogen decreases brain volumes of MTF transsexuals subjects towards female proportions (Hulshoff Pol et al., 2006).
To extend these prior findings while overcoming some of their limitations, we investigated variations in brain structure in 60 control subjects (30 males, 30 females) and 24 MTF transsexuals who had not been treated with female hormones. More specifically, we used magnetic resonance imaging (MRI) to investigate neuroanatomy at high-resolution in vivo, and applied a sophisticated computational image analysis approach to compare regional volumes of gray matter throughout the brain.
Section snippets
Subjects
Twenty-four MTF transsexuals were recruited through fliers provided to local transsexual community organizations and to professionals who offer services to the transsexual community. Thirty male and thirty female control subjects were selected from the International Consortium for Brain Mapping (ICBM) database of normal adults (http://www.loni.ucla.edu/ICBM/Databases/). The mean age (SD) of the MTF transsexuals was 46.73 (13.18) years with an age range between 23 and 72 years. Male and female
Results
As demonstrated in Fig. 1, we detected significant differences between MTF transsexuals, males, and females in a large number of regions across the brain. More specifically, within the frontal lobe, we observed gray matter volume differences bilaterally in the superior frontal gyrus, close to midline and also at the frontal pole, as well as within the right orbital gyrus. Furthermore, we noticed pronounced gray matter volume differences bilaterally across the occipital and posterior temporal
Discussion
Overall, our study provides evidence that MTF transsexuals possess regional gray matter volumes mostly consistent with control males. However, the putamen was found to be “feminized” in MTF transsexuals. That is, the gray matter volume of this particular structure in the MTF transsexual group was both larger than in males and within the average range of females. Interestingly, in a positron emission tomography (PET) study, it was demonstrated that the left putamen in a sample of MTF
Acknowledgments
This work was supported by the National Institutes of Health through the NIH Roadmap for Medical Research, grant U54 RR021813 entitled Center for Computational Biology (CCB). Information on the National Centers for Biomedical Computing can be obtained from <http://nihroadmap.nih.gov/bioinformatics>. Additional support was provided by the NIH/NCRR resource grant P41 RR013642, Dr. Sánchez's NIH training grant 5 T32 HD07228: 26, Dr. Gaser's BMBF grant 01EV0709, and Dr. Narr's NIH K-award MH073990.
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