EDIT: Please do keep in mind that this article was written in 2011. Its information and language usage may be old.

Brain Differences between Transsexuals and Cissexuals

Transsexuality is commonly defined as a severe form of gender dysphoria in which the transsexual person desires to medically transition to the opposite sex. Transsexuality is currently listed as both a psychiatric diagnosis (American Psychological Association, 1994) and a medical diagnosis (World Health Organization, 1992). Regardless of its dual status, the only effective treatment for transsexuality is medical transition, which commonly includes cross-gender hormone therapy (HRT), sexual reassignment surgery, behavioral training, and “cosmetic” treatments like electrolysis, facial surgery, or breast augmentation.

The etiology of transsexuality is unknown and heavily debated. Thorough examination of transsexual persons has failed to find an endocrinological cause (Gooren, 2006). Psychiatric explanations (e.g., “autogynephilia”; Blanchard, 2005) have been rejected as incomplete, offensive, and unscientific by some in the scientific and transsexual communities (Moser, 2010). Now, some researchers are focusing on the brain to try to explain the differences between transsexual people and cissexual (i.e., not transsexual) people.

Two basic kinds of examination of the brain have been performed so far: a) physical studies of brains acquired by the Netherlands Brain Bank, and b) imaging studies (e.g., magnetic resonance imaging).

Brain Slice Studies

These studies stained brain sections acquired from the Netherlands Brain Bank and examined neuron count and volume. No effect of cause of death, age at death, or age of the brain were noted. The transsexual brains in these studies had all had HRT, although some had not had hormones in several years before death due to illness (e.g., cancer). Most had had some form of sexual reassignment surgery (e.g., orchidectomy).

The first study to examine brain differences between transsexuals and cissexuals was in 1995 (Zhou, Hofman, Gooren, and Swaab). They chose to focus on neuron number and volume in the center subdivision of the bed nucleus of the stria terminalis (BSTc). The BSTc has been observed to be sexually dimorphic. Zhou et al specifically examined vasoactive intestinal polypeptide innervation in this area.

Zhou et al (1995) affirmed that cissexual men had larger BSTc volumes than cissexual women, and that transsexual women had volumes similar to those of cissexual women and dissimilar to those of cissexual men. This effect did not appear to be associated with cause of death, sexual orientation, AIDS status at time of death, or age at death.

Crucially, this effect also does not appear to be due to HRT. First, several of the transsexual women had ceased HRT several years before death and their BSTc volumes were not different from those of the other transsexual women. Second, the subject pool included cissexual men and cissexual women whose adult hormones had changed (e.g., orchidectomy, menopause, adrenal tumors) and their BSTc volumes were in the cissexual male and cissexual female ranges, respectively.

The work done by Zhou et al (1995) was expanded upon by Kruijver et al (2000). This more recent study examined the somatostatin (SOM) innervation in the BSTc. They found similar results; cissexual men had more SOM neurons than cissexual women. Transsexual women had similar numbers to cissexual women, and the single brain from a transsexual man had similar numbers to cissexual men. Similar to Zhou et al (1995), Kruijver et al (2000) did not find any effect of adult hormones. This study also included the brain from a man who had gender dysphoria but never transitioned or had HRT. His SOM BSTc neuron numbers were in the same range as post-transition transsexual women and cissexual women.

Kruijver et al (2000) theorize that, because there was apparently no effect of sex hormone changes in adulthood on neuron numbers or volume in the BSTc, sexual dimorphism in that area must be established before adulthood. Chung, De Vries, and Swaab (2002) explored sexual differentiation of the BSTc; specifically, they examined VIP innervation, SOM innervation, and total BSTc volume. They examined the BSTc regions in brains from infants, children/adolescents, and adults. All the subjects in this experiment were from cissexual men and women. Chung et al found that the BSTc did not sexually differentiate until “adulthood” (i.e., somewhere between ages 16 and 28, those being the oldest and youngest of the adolescent and adult brains, respectively), supporting the ideas of Kruijver et al (2000). This finding implies that the BSTc is not the only sex differentiated brain area that influences gender identity. Transsexuals have reported cross-gender feelings at ages much younger than adulthood. If BSTc differences were the only cause of transsexuality, transsexuals would not report cross-gender feelings until adulthood.

Garcia-Falgueras and Swaab (2008) focused on the interstitial nucleus of the anterior hypothalamus (INAH) 3 instead of the BSTc. Their results were very similar to those in the BSTc: cissexual men had more neurons and volume than cissexual women, and transsexual women were similar to cissexual women. Unlike studies of the BSTc, they found that castrated men has values between those of cissexual men and women, and they found no change in the INAH3 of cissexual women pre- and post- menopause. A drop in adult testosterone in a cissexual man appears to affect his INAH3, but not so much as to make the INAH3 the same size as a cissexual woman. Therefore, HRT cannot be the sole cause of the similarity between the INAH3 of cissexual and transsexual women.

The INAH3 is in the sexually dimorphic nucleus, and thus presents an interesting contrast to the BSTc. Unlike the BSTc, which only sexually differentiates in adulthood, the sexually dimorphic nucleus becomes differentiated in humans age two to four (Gooren, 2006). However, conclusions that can be drawn from INAH3 data are less clear, as the INAH3 clearly responds to changes in adult hormone levels.

In summary, brain slice studies have examined two sexually dimorphic areas of the brain: the BSTc and the INAH3. The structures of both in transsexual women resemble those of cissexual women, not cissexual men. This suggests a biological basis to transsexualism.

The potential effect of HRT on the BSTc and INAH3 cannot be completely ignored. The BSTc appears to be nonresponsive to hormone changes in adults and only differentiates in early adulthood. Therefore its sexual dimorphism is less likely to be either the cause of gender identity, or the effect of HRT. The INAH3 appears to be somewhat but not completely responsive to hormone changes in adults, and differentiates in early childhood. Its role in gender identity and transsexuality is less clear.

Brain Imaging Studies

The brain imaging studies that have been performed so far have been able to examine both pre-transition transsexuals and transsexuals in transition.

Berglund, Lindstrom, Dhejne-Helmy and Savic (2008) focused on the limbic response of the brain to odorous sex steroids, specifically 4,16-androstadien-3-one (ANDR) and estra-1,3,5(10),16-tetraen-3-ol (ESTR). They used positron emission tomography to examine the activation pattern, and focused on the hypothalamus and “olfactory brain” (i.e. the amygdala, piriform cortex, anterior insular- and anterior cingulate cortex).

Cissexual women and cissexual men responded differently to the steroids. When smelling ANDR, cissexual women had hypothalamic activation and cissexual men had olfactory activation. Conversely, when smelling ESTR, cissexual women had olfactory activation and cissexual men had hypothalamic activation. Berglund et al (2008) found that pre-transition transsexual women had activation patterns similar to cissexual women; they had hypothalamic activation in response to ANDR and olfactory activation in response to ESTR.

Berglund et al (2008) controlled for sexual orientation because they used odorant steroids; the study’s cissexual women were androphilic, and cissexual men and transsexual women were gynephilic. The activation patterns in transsexual women were more similar to those who shared their gender identity, cissexual women, than to those who shared their sexual orientation, cissexual gynephilic men. However, it is worth pointing out that this was not empirically tested; transsexual women were not compared to androphilic cissexual men or gynephilic cissexual women.

Rametti et al (2011) examined differences in white matter tracts with diffusion tensor imaging. They affirmed that there was a cissexual sex difference, but unlike the previous studies, did not find that pre-transition transsexual women were like cissexual women. Instead, they found that transsexual women were statistically significantly different from both cissexual men and women and were somewhere in between the two. One could thus conclude that the white matter tracts in pre-HRT transsexual brains are partially feminized or partially masculinized.

Pol et al (2006) examined brain and hypothalamic volume over time as transsexual men and women transitioned, and compared those volumes to those of cissexual men and women. Before treatment, transsexual women’s volumes were like cissexual men’s and transsexual men’s volumes were like cissexual women’s; the volume of the former group was larger than that of the latter group. After four months of HRT, the transsexual women’s total brain volume decreased and their third and lateral ventricle volumes increased. Likewise, the transsexual men’s total brain volume increased and their third and lateral ventricle volumes decreased. That is, the total brain volume of both groups changed away from their sex at birth to the sex matching their gender identity.

Results from these brain imaging studies are less easy to interpret than results from the brain slice studies. Transsexual women’s brains appear to react similarly to cissexual women’s to odorous sex steroids. Conversely, transsexual women do not appear to be like cissexual women with regards to their white matter tracts or brain volume. The white matter tracts of pre-transition transsexual women appear to be between those of cissexual men and women. Like the INAH3, then, the white matter tracts reflect a partial feminization/masculinization that is difficult to interpret. Brain volume appears to follow biological sex rather than gender identity and appears to be influenced by hormonal transition. One can conclude, then, that brain volume is controlled by sex hormones and is not necessarily indicative of gender identity.

Conclusion

The amount of research that has been completed on the differences between transsexual and cissexual brains is small, but suggestive. Some areas of the brain appear to be sexually dimorphic irrespective of genetics or hormones (e.g., BSTc), whereas others appear to be more dependent upon sex hormones (e.g., brain volume). From the results of these studies, one may infer that pre-transition transsexual women’s brains are feminine in the BSTc and INAH3, partially feminine in their white matter tracts, and masculine in total brain and hypothalamic volume. Data in transsexual men is rarer because these studies are conducted in the western world, where transsexual women outnumber transsexual men (Gooren, 2006). However, studies of transsexual men appear to imply that the reverse is true for them.

These studies have numerous limitations. First, they have yet to be replicated. Replication is needed to ensure reliability and generalizability of these results. Second, these studies (especially those involving deceased brains) have small numbers of subjects, especially for the transsexual subjects. Studies involving brains from the Netherlands Brain Bank typically had fewer than 10 transsexual brains to study, and the latter two (Kruijver et al, Chung et al) only had a single transsexual male brain. Although fewer numbers of subjects are generally more acceptable in biological research than in psychological research, it is still a potential source of error.

Potentially the most glaring limitation in these studies is their conflation of sexual orientation and gender identity. Berglund et al (2008), for example, only compared heterosexual cissexual women and men with gynephilic/homosexual transsexual women. While they could not include androphilic/heterosexual transsexual women in their study because of rarity, they failed to include homosexual cissexual men and women as comparison groups. This introduces a potentially confounding variable.

Despite these limitations, evidence so far is suggestive of a biological influence in transsexuality. More research is needed to confirm and expand these preliminary findings.

References

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.

Berglund, H., Lindstrom, P., Dhejne-Helmy, C., & Savic, I. (2008). Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling odorous steroids. Cerebral Cortex, 18, 1900-1908.

Blanchard, R. (2005). Early history of the concept of autogynephilia. Archives of Sexual Behavior, 34, 439–446.

Chung, W. C. J., De Vries, G. J., & Swaab, D. F. (2002). Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. The Journal of Neuroscience, 22, 1027-1033.

Garcia-Falgueras, A., & Swaab, D. F. (2008). A sex difference in the hypothalamic uncinate nucleus: Relationship to gender identity. Brain, 131, 3132-3146.

Gooren, L. (2006). The biology of human psychosexual differentiation. Hormones and Behavior, 50, 589-601.

Kuijver, F. P M., Zhou, J. Pool, C. W., Hofman, M. A., Gooren, L. J. G., & Swaab, D. F. (2000). Male-to-female transsexuals have female neuron numbers in a limbic nucleus. The Journal of Clinical Endocrinology and Metabolism, 85, 2034-2041.

Moser, C. (2010). Blanchard’s autogynephilia theory: A critique. Journal of Homosexuality, 57, 790-809.

Pol, H. E. H., Cohen-Kettenis, P. T., Van Haren, N. E. M., Peper, J. S., Brans, R. G. H., Cahn, W. et al (2006). Changing your sex changes your brain: Influence of testosterone and estrogen on adult human brain structure. European Journal of Endocrinology, 155, S107-S114.

Rametti, G., Carrillo, B., Gomez-Gil, E., Junque, C., Zubiarre-Elorza, L., Segovia, S. et al (2011). Journal of Psychiatric Research, 45, 949-954.

World Health Organization. (1992). Tenth revision of the international classification of disease. Geneva: Author.

Zhou, J., Hofman, M. A., Gooren, L. J. G., & Swaab, D. F. (1995). A sex difference in the human brain and its relation to transsexuality. Nature, 378, 68-70.

This paper is copyright Rose Lovell, 2011.

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