White Matter and (Trans)Sexual Differentiation

From New Scientist:

Transsexual differences caught on brain scan

Antonio Guillamon's team at the National University of Distance Education in Madrid, Spain, think they have found a better way to spot a transsexual brain. In a study due to be published next month, the team ran MRI scans on the brains of 18 female-to-male transsexual people who'd had no treatment and compared them with those of 24 males and 19 females.

They found significant differences between male and female brains in four regions of white matter – and the female-to-male transsexual people had white matter in these regions that resembled a male brain (Journal of Psychiatric Research, DOI: 10.1016/j.jpsychires.2010.05.006). "It's the first time it has been shown that the brains of female-to-male transsexual people are masculinised," Guillamon says.

In a separate study, the team used the same technique to compare white matter in 18 male-to-female transsexual people with that in 19 males and 19 females. Surprisingly, in each transsexual person's brain the structure of the white matter in the four regions was halfway between that of the males and females (Journal of Psychiatric Research, DOI: 10.1016/j.jpsychires.2010.11.007). "Their brains are not completely masculinised and not completely feminised, but they still feel female," says Guillamon.

The articles are:

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study Rametti et al Journal of Psychiatric Research, Volume 45, Issue 2, February 2011, Pages 199-204

- which I've blogged about before, and

The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study Rametti et al Journal of Psychiatric Research, In Press, Corrected Proof, Available online 30 December 2010

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.

While we're on the subject, another good article.

Sexual differentiation of the human brain in relation to gender identity and sexual orientation, Savic et al Progress in Brain Research, Volume 186, 2010, Pages 41-62 (Chapter 4)

There is a vast array of factors that may lead to gender problems (Table 1). Twin and family research has shown that genetic factors play a part ([Coolidge et al., 2002], [Gómez-Gil et al., 2010a], [Hare et al., 2009] and [van Beijsterveldt et al., 2006]). Rare chromosomal abnormalities may lead to transsexuality (Hengstschläger et al., 2003) and it was found that polymorphisms of the genes for ERα and ERβ, AR repeat length polymorphism and polymorphisms in the aromatase or CYP17 gene also produced an increased risk ([Bentz et al., 2008], [Hare et al., 2009] and [Henningsson et al., 2005]).
Abnormal hormone levels during early development may play a role, as suggested by the high frequency of polycystic ovaries, oligomenorrhea and amenorrhea in female-to-male (FtM) transsexuals. This observation suggests early intrauterine exposure of the female fetus to abnormally high levels of testosterone (Padmanabhan et al., 2005 V. Padmanabhan, M. Manikkam, S. Recabarren and D. Foster, Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female, Molecular and Cellular Endocrinology 246 (2005), pp. 165–174.Padmanabhan et al., 2005). A recent study did not confirm a significantly increased prevalence of polycystic ovary syndrome. However, there was a significantly higher prevalence of hyperandrogynism in FtM transsexuals, also indicating the possible involvement of high testosterone levels in transsexuality (Mueller et al., 2008). A girl with congenital adrenal hyperplasia (CAH), who has been exposed to extreme levels of testosterone in utero, will also have an increased chance of becoming transsexual. Although the likelihood of transsexuality developing in such cases is 300–1000 higher than normal, the risk for transsexuality in CAH is still only 1–3% (Zucker et al., 1996), whereas the probability of serious gender problems is 5.2% (Dessens et al., 2005). The consensus is, therefore, that girls with CAH should be raised as girls, even when they are masculinized (Hughes et al., 2006).

Epileptic women who were given phenobarbital or diphantoin during pregnancy also have an increased risk of giving birth to a transsexual child. Both these substances change the metabolism of the sex hormones and can act on the sexual differentiation of the child’s brain. In a group of 243 women who had been exposed to such substances during pregnancy, Dessens et al. (1999) found three transsexual children and a few others with less radical gender problems; these are relatively high rates for such a rare condition. On the “DES” (diethylstilbestrol, an estrogen-like substance—see later) children’s website they claimed that transsexuality occurs in 35.5% and a gender problem in 14% of the DES cases (links [Gender Identity Research and Education Society] and [DES Sons’ International Research] webpages). This is alarming, but needs, of course, to be confirmed in a formal study. There are no indications that postnatal social factors could be responsible for the occurrence of transsexuality (Cohen-Kettenis et al., 1998).

And rather a lot more.

We're now no longer answering the question "is cross-sexed neuro-anatomy causal of transsexuality?", we're identifying exactly which bits of the brain are affected, to what degree, and with what effects.