The Brain of Male-to-Female Homosexual Transsexuals Before Cross-Sex Hormone Treatment

Volume and Brain Compartments

MRI studies show that ICV in adult (Rametti et al., 2011b) and adolescent (Hoekzema et al., 2015) untreated homosexual MtFs is similar to male controls’. Moreover, GM, WM, and CSF volumes in homosexual MtFs do not differ from those of control males and are significantly greater than those of control females (Table 4).

Table 4 Brain volume of untreated homosexual male-to-female transsexuals Full size table

Cortex

There are two volumetric studies of the cortex using voxel-based morphometry (VBM) in adolescent and adult untreated MtFs (Table 5). These studies compare MtFs with male and female controls that show sex differences. Simon et al. (2013) have studied a small sample of untreated homosexual MtFs. Homosexual MtFs and female controls had less gray matter volume in the left somatosensory and primary motor cortices as well as the posterior cingulate and calcarine gyri and the precuneus than male controls and FtMs. These findings suggest that homosexual MtFs have a feminine cortical pattern. However, the results should be taken cautiously because of the small sample size and the brain statistical maps showing significance were at an uncorrected level (p < .001).

Table 5 The cortex and the white matter of untreated homosexual male-to-female transsexuals Full size table

More recently, the gray matter of untreated androphilic GD adolescents has been addressed (Hoekzema et al., 2015). MtFs have smaller volume than male controls in the left superior posterior hemisphere of the cerebellum and smaller volume than female controls in the right inferior orbitofrontal cortex. Thus, untreated MtF adolescents differ from both male and female controls in some cortical regions.

CTh has also been used to investigate brain differences in transsexuals (Table 5). Zubiarre-Elorza et al. (2013) compared early-onset untreated homosexual MtFs with female and male controls. MtFs did not differ in CTh from female controls but their CTh was greater than that of control males in the orbitofrontal, insular, and medial occipital regions of the right hemisphere. This report was the first to show the feminization of large portions of the cortex in early-onset homosexual MtFs and it concluded that MtFs had a feminine cortical thickness but differed from control males in regions that female controls did not (Table 5; Fig. 2b).

Fig. 2 Cortical thickness of untreated homosexual male-to-female (MtF) and female-to-male (FtM) transsexuals. Upper panel: (a) comparison between male and female controls. Bottom panel: (b) comparison between MtF and male controls; c comparison between FtM and male controls. All significant comparisons showed the F > M pattern. Note that both MtFs (b) and FtMs (c) show a feminine pattern although they differ in different regions from males than do control females. L left hemisphere, R right hemisphere. Zubiaurre-Elorza, Junque, Gómez-Gil, Segovia, Carrillo & Guillamon, 2013, with permission Full size image

White matter

Recently, white matter microstructure has been studied in early-onset homosexual MtFs using DTI (Table 5; Fig. 3a). There are sex differences in FA, males showing greater FA values in important brain fascicles such as the right and left superior longitudinal fasciculi (rSLF; lSLF), the inferior fronto-occipital fasciculus (IFOF), the cingulum (Cin), the forceps minor (Fm), and the corticospinal tract (CST) (Rametti et al., 2011b). Interestingly, early-onset homosexual MtFs show demasculinized FA in all these brain fascicles because their FA values were statistically different from the values for both the male and female control groups. The MtF IFOF is masculine because its FA did not differ from male controls’. Curiously, the demasculinized fascicles seem to be restricted to the right hemisphere (Table 5; Rametti et al., 2011b).

Fig. 3 Histograms showing fractional anisotropy mean values (FA) of untreated homosexual male-to-female (MtF) and female-to-male (FtM) transsexuals and male (M) and female (F) controls. Upper panel: (a) FA values in MtF differ significantly from females in all six comparisons, and from males in only five out of the six. Bottom panel: (b) FA values in FtMs differ significantly from females in all four comparisons, from males in only one out of the four. SLF superior longitudinal fasciculus (r right, l left), IFOF inferior fronto-occipital fasciculus. Rametti et al. 2011a and 2011b, with permission Full size image

Conclusions

Overall, in vivo MRI studies indicate that the main morphological parameters of the brain (ICV, GM, WM, and CSF) are congruent with their natal sex in untreated homosexual MtFs. However, some cortical regions show feminine volume and thickness and it should be underscored that CTh presents an F > M morphological pattern. Nevertheless, with respect to CTh, this feminine cortical pattern is not the same as the one shown by control females (compare Fig. 2a and b). On the other hand, the main white matter fascicles in MtFs are demasculinized, while others are still masculine (Fig. 3a). Moreover, most of the differences appear to be located in the right hemisphere. So far, the studies on the white matter, like those above on gray matter, strongly suggest that MtFs have their own brain phenotype that mainly affects the right hemisphere.

The Brain of Nonhomosexual Male-to-Female Transsexuals Before Cross-Sex Hormone Treatment

All we know about the morphology of the brain of nonhomosexual MtFs comes from a single VBM study (Savic & Arver, 2011). Nonhomosexual MtFs have the same total intracranial volume as control males. They also show a larger gray matter volume in cortical regions in which the male and female controls did not differ in the study. These regions were the right parieto-temporal junction, the right inferior frontal, and the insular cortices. It was concluded that their data did not support the notion that the nonhomosexual MtF brain was feminized.

With respect to subcortical structures, it was reported that untreated nonhomosexual MtFs had a relatively smaller putamen and thalamus than male and female controls although these two latter groups did not show sex differences in the two structures (Savic & Arver, 2011).

In summary, the cortex of nonhomosexual MtFs presents morphological peculiarities in regions in which male and female controls do not differ.

The Brain of Female-to-Male Transsexuals Before Cross-Sex Hormone Treatment

Brain Morphology

Although there are few works on the brain morphology of FtMs as yet, several studies have described the gray and white matter of untreated homosexual FtMs. These works can give us an initial approach to the morphology of their brain (Rametti et al., 2011a; Zubiaurre-Elorza et al., 2013). In regards to the gross morphology, the intracranial volume of adolescent FtMs is similar to female controls’ (Hoekzema et al., 2015).

There are only two works using VBM (Table 6). Simon et al. (2013) studied seven homosexual FtMs and found that these subjects and their male controls had larger volumes than female controls and MtFs in the left gyri: pre- and postcentral; posterior cingulate; and calcarine as well as the precuneus regions. These observations indicate that certain regions of the left hemisphere are masculine in FtMs. But the statistical maps were uncorrected.

Table 6 The cortex, subcortical structures, and white matter microstructure of untreated homosexual female-to-male transsexuals Full size table

Untreated androphilic adolescent FtMs have also been studied (Hoekzema et al., 2015), and they show less volume in the left superior medial frontal cortex than control females and less in the right insula than control males; this study shows that certain regions of the cortex of adolescent FtMs are different from both male and female controls.

There is only one study of cortical thickness in early-onset homosexual FtMs (Table 6; Fig. 2c). Their CTh does not differ statistically from female controls but it does differ significantly from some regions in male controls in which male and female controls do not differ in CTh. Contrary to control females, FtMs showed significantly greater CTh than males in the left parieto-temporal cortex but, unlike control females, they did not differ from control males in the prefrontal orbital region (Fig. 2c; Zubiaurre-Elorza et al., 2013).

With respect to subcortical structures (Table 6), the volume of the putamen is larger in male than in female controls, but in homosexual FtMs the volume is masculinized, being similar to that of control males and differing from the volume of control females (Zubiaurre-Elorza et al., 2013).

White matter microstructure has been studied in homosexual FtMs using DTI (Table 6). It was reported that brain bundles involved in cognitive and emotional behavior were masculinized in homosexual FtMs (Fig. 3b). Males have greater FA values than female controls. FtM FA values are significantly greater than those of female controls and similar to those of male controls in the anterior and posterior right SLF and Fm. However, their CST is defeminized; that is, FtM FA values lie just between male and female controls and are significantly different from each of these two groups (Rametti et al., 2011a).

Conclusions

In FtMs, the gross morphological parameters correspond to their natal sex; their cortex is generally feminine but differs from males in different regions than do control females (compare Fig. 2a and c). Furthermore, some brain bundles are masculinized (Fig. 3b). All these findings suggest that homosexual FtMs have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure. Moreover, these changes are mostly seen in the right hemisphere.

The Brain of Untreated Male-to-Female and Female-to-Male Transsexuals from Mixed Samples of Homosexual and Nonhomosexual Subjects

Some studies in the literature have used groups of mixed samples of MtFs in regard to their sexual orientation and this aspect was also unspecified in their control groups (Luders et al., 2009b, 2012). Others mix homosexual and nonhomosexual MtFs and FtMs and use a gathering of heterosexual, homosexual, and bisexual subjects as controls (Hahn et al., 2015; Kranz et al., 2014). These studies are very difficult to interpret and any comparison with the structural data presented in the previous sections, studying homogeneous groups of homosexual or nonhomosexual MtFs or FtMs, could confuse the picture of the brain structure of MtFs and FtMs in the context of the expression of sex differences. Nevertheless, they are summarized in Table 7.

Table 7 Gray and white matter in studies with mixed samples of untreated homosexual and nonhomosexual male-to-female and female-to-male transsexuals Full size table

The study of mixed samples implicitly assumes that transsexuals are a homogeneous group. This is far from the truth with respect to the onset of GD and sexual orientation (Blanchard, 1989a, 1989b). Moreover, sexual orientation is associated to different body phenotypes. Homosexual MtFs are shorter than men in the general population, whereas nonhomosexual MtFs have been reported to be similar in height to control males (Blanchard, Dickey, & Jones, 1995). Although a later study found no significant differences regarding body mass between homosexual and nonhomosexual MtFs, other distinctive developmental and behavioral characteristics (age of onset; cross-dressing, having been married, cross-gender appearance) have been described for each subtype of transsexual (Smith et al., 2005). Finally, from the studies of Savic’s group, we know that homosexual persons show phenotypic characteristics in cortical and subcortical structures. Homosexual males and heterosexual females had thinner cortices primarily in visual areas and smaller thalamus volumes than heterosexual males (Abé, Johansson, Allzén, & Savic, 2014). Moreover, in contrast to heterosexual males, and in congruence with heterosexual females, homosexual males displayed hypothalamic activation in response to a putative male pheromone (Savic, Berglund, & Lindstrom, 2005). These observations signify that control groups in studies of the transsexual brain must be homogenous in regards to sexual orientation. Nevertheless, it is possible to extract some data from these studies if we compare those that use the same MRI techniques and measurements.

The volumetric study by Luders et al. (2009b) found that the pattern of GM variation in MtFs was more similar to the pattern found in men than in women (Table 7). They studied a mixed sample of homosexual and nonhomosexual MtFs. The Savic and Arver (2011) volumetric study of nonhomosexual MtFs reported that their brains were not feminized. It could be that in Luders et al.’s (2009b) study there were more nonhomosexual than homosexual MtFs and, as a result, the two studies reached the same conclusion, in contrast to the volumetric study of Simon et al. (2013) that reported cortical feminization in homosexual MtFs.

It is practically impossible to compare the two studies on CTh in MtFs because of the differences in their samples and designs. Luders et al. (2012) did not specify sexual orientation in either their transsexual or their control group and used only males as controls, while Zubiaurre-Elorza et al.’s (2013) study design employed male and female heterosexual controls to study homosexual MtFs.

In regard to white matter microstructure, the study of Kranz et al. (2014) mixed sexual orientation within their MtF, FtM, and female and male control groups (Table 7). The differences in design and sampling make it almost impossible to compare these studies with those of our group (Rametti et al., 2011a, 2011b; see Tables 5, 6, 7). However, since in Kranz et al.’s study most of the FtMs were homosexuals (19/24), it could feasibly be compared with the results of Rametti et al. (2011a) presented in the previous section (Table 6). Kranz et al. did not find FA differences between FtMs and control groups but they did find significantly decreased MD values in FtMs with respect to control females in the same tracts with increased FA values in FtMs (Rametti et al. 2011a; Table 6). Thus, MD results also indicate a defeminization or masculinization of the white matter microstructure in FtMs, as was reported by Rametti et al. (2011a).

With the same design and sample as in Kranz et al., structural connectivity has been studied from DTI using graph theory (Hahn et al., 2015). The study reported that FtMs, with respect to male and female controls and MtFs, have decreased intra-hemispheric connectivity between the right subcortical/limbic and right temporal lobes (Table 7). Interestingly, the changes in brain connectivity found in FtMs and MtFs are in opposite directions and are only seen in the right hemisphere.

Recently, resting-state fMRI was used to study the similarities between spontaneous brain connectivity in one untreated FtM of unspecified GD onset and sexual orientation with polycystic ovary syndrome and male and female controls. This FtM subject showed a functional connectivity profile that was comparable to that of the subject’s natal sex (Santarnecchi, Vatti, Dettore, & Rossi, 2012).

Theoretical and Functional Implications of the Brain Phenotype of Untreated Homosexual Transsexuals

Untreated homosexual MtFs and FtMs show a complex picture for the expression of sex differences in their brains (Tables 5, 6). Contrary to some popular ideas, the MtF brain is not completely feminized but presents a mixture of masculine, feminine, and demasculinized traits. This is better illustrated by the data on CTh and FA (Table 8). Moreover, the brain of homosexual FtMs is not uniformly masculinized but presents a mixture of feminine, defeminized, and masculinized morphological traits (Table 9). For both MtFs and FtMs, the morphological traits observed depend on the region and the type of measurement taken. Thus, the morphology of the brain of homosexual MtFs and FtMs strongly suggests that each one has its own phenotype, and that the phenotype is different from those of heterosexual males and females.

Table 8 The brain phenotype of untreated homosexual male-to-female transsexuals from studies of cortical thickness and white matter microstructure Full size table

Table 9 The brain phenotype of untreated homosexual female-to-male transsexuals from studies of cortical thickness and white matter microstructure Full size table

In terms of psychological presentation, people with an early onset of GD have much in common with individuals with somatic intersexuality (Meyer-Bahlburg, 2011). None of the above neuroimaging studies included subjects with signs of somatic intersexuality. MtFs and FtMs each have their own cerebral phenotype. This would suggest that early-onset homosexual transsexuals have an intersex condition restricted to the brain. “Brain hermaphroditism” was suggested in the early postmortem studies (Kruijver, Zhou, Pool, Hofman, Gooren, & Swaab, 2000).

It has been pointed out that verifying this hypothesis requires corroborating at least one of the genetic, hormonal, or morphological lines of research into some specific effect by hormones that would affect brain organization of sexual differences but not other organs (Meyer-Bahlburg, 2011, 2013). The existing findings on brain changes fulfill at least one of the conditions and provide evidence that the brain structures are already affected in still untreated homosexual MtFs and FtMs. Moreover, in androgenized FtMs, FA value increases in the SLF and the CST can be predicted by the free testosterone index before the treatment begins (Rametti et al., 2012). All these findings support the intersex hypothesis of transsexuality.

The right-side asymmetry in the differences between MtFs, FtMs, and control males (Tables 8, 9) focuses attention on that hemisphere. Sex differences in functional hemispheric lateralization are well known. Transsexuals have been studied from this perspective, especially in relation to mental rotation and handedness, because these may be influenced by prenatal androgen levels, which would reflect some developmental anomaly. Laboratory animal experiments with rats suggest that cerebral cortical laterality differs between the sexes and that gonadectomy at birth will alter the usual cortical laterality (Diamond, 1991).

The right hemisphere is involved in mental rotation and males outperform females (Voyer, Voyer, & Bryden, 1995). Mental rotation performance in untreated early-onset homosexual MtFs and FtMs is consistent with that of their natal sex and not with that of their gender identity (Haraldsen, Opjordsmoen, Egeland, & Finset, 2003). This is also reflected by the finding that untreated MtFs perform better than untreated FtMs in these tasks (Slabbekoorn, van Goozen, Gooren, & Cohen-Kettenis, 2001). However, there are reports in which transsexual groups show a pattern of performance that is different from their biological sex (Cohen-Kettenis, van Goozen, Doorn, & Gooren, 1998). The pattern of brain activation in mental rotation involves the frontal, parietal, and posterior occipital regions (Carrillo et al., 2010; Cohen et al., 1996; Hugdahl, Thomsen, & Ersland, 2006). Untreated MtFs and FtMs show parietal activation (Sommer et al., 2008). The fronto-parietal-occipital pattern of activation is also seen in early-onset homosexual MtFs and FtMs after long-term cross-sex hormone treatment (Carrillo et al., 2010). At present, it is not possible to relate changes observed in the right cortex and fascicles of transsexuals (Tables 8, 9) with differences in mental rotation abilities. However, the superior longitudinal fasciculus, which connects fronto-parietal regions, is demasculinized in MtFs and masculinized in FtMs. Moreover, the right parietal region is thicker in FtMs than in males, while MtFs present a thicker cortex than males in visuoperceptive occipital regions (cuneus and pericalcarine regions) (see Fig. 2b, c). We are still far from being able to relate these morphological differences to spatial abilities in transsexuals.

Hand preference has also been studied in transsexuals (Green & Young, 2001). Sex differences in hand preference are well known, left-handedness being more common in males than females (McGlone, 1980). In young boys and girls, prenatal testosterone exposure was related to a decrease in strength of handedness (Lust et al., 2011). Pre-pubertal boys with GD were more often left-handed than control males (Zucker, Beaulieu, Bradley, Grimshaw, & Wilcox, 2001). This is also seen in adult MtFs and FtMs before (Cohen-Kettenis et al., 1998) and after cross-sex hormone treatment (Green & Young, 2001; Orlebeke, Boomsma, Gooren, Verschoor, & Van Den Bree, 1992; Watson & Coren, 1992; Wisniewski, Prendeville, & Dobs, 2005). This would suggest a different pattern of cerebral hemispheric organization in transsexuals.

The CST is the most important motor tract with fibers originating in motor, premotor, and sensory cortices (Lemon, 2008). Studies using DTI techniques have shown that the CST exhibits a leftward asymmetry (Dubois et al., 2009; Westerhausen, Huster, Kreuder, Wittling, & Schweiger, 2007) that is present as early as 4 months of life (Dubois et al., 2009) and seems to be unrelated to hand preference (Nathan, Smith, & Deacon, 1990; Westerhausen et al., 2007). However, a study of the CST in 400 adolescents (12–18 years old) found that this tract, at the level of the internal capsule, shows a strong left > right hemispheric asymmetry that is less marked in left-handed subjects (Herve et al., 2009). Moreover, CST increases in this region in males but not in females, so the increases must be related to the plasma levels of testosterone (Herve et al., 2009). Using DTI techniques, it was found that early-onset homosexual MtFs have a demasculinized CST (Rametti et al., 2011b), while, in early-onset homosexual FtMs, this tract is masculinized (Rametti et al., 2011a). DTI studies of CST microstructure in transsexuals are a first step and signal a new direction for future explorations of hand preference in transsexuals.

Results on cortical thickness also suggest that this parameter would be a good target for a systematic study on body perception mechanisms in MtFs and FtMs. The right hemisphere is mainly involved in the analysis of body perception and its emotional connotations (Longo, Azanon, & Haggard, 2010). It was underscored above that the main brain differences shown by transsexuals are located in the right hemisphere. Generally, the emergence of a masculine or feminine identity must be strongly mediated by the early development of a male or female body self-perception. This requires several levels of construction of somatoperception and somatorepresentation; the latter includes emotions, attitudes directed towards one’s own body, and the link between the physical body and the psychological self (Longo et al., 2010). The body model of identity integrity would implicate a right fronto-parietal and insular network (Giummarra, Bradshaw, Nicholls, Hilti, & Brugger, 2011) and differences have been reported for homosexual MtFs and FtMs in all these regions (Zubiaurre-Elorza et al., 2013).

The literature on body perception in transsexuals reflects two approaches. One comes from an analysis of the desire to amputate a limb as a type of identity disorder (First, 2005) and the other is a theoretical hypothesis generated from the analysis of the phantom limb phenomenon (Ramachandran & McGeoch, 2007).

It has been suggested that the desire for limb amputation could be similar to transsexualism because in most cases the goal of amputation is to match one’s body to one’s identity (First, 2005). The similarities with transsexuals are mainly associated with the feeling of being uncomfortable with an aspect of one’s anatomical identity. It should be remembered that some transsexuals not only reject the masculine or feminine aspects of their bodies but they dislike specific regions (i.e., breasts in FtMs and genitals in MtFs). This body uneasiness experienced by transsexuals diminishes after cross-sex hormone treatment (Fisher et al., 2014). In addition, the desire for limb amputation has an early onset in childhood or adolescence and a significant subgroup of these individuals experiences sexual arousal by fantasizing about the desired limb amputee identity (First, 2005).

The theoretical parallel between the desire for limb amputation and transsexuality has been analyzed by Lawrence (2006). Nonhomosexual but not homosexual MtFs seem to share some characteristics with those who desire limb amputation. It should be noted that in most cases subjects want a left-limb amputation (First, 2005) and this may reflect some dysfunction in the right hemisphere, precisely the hemisphere in which homosexual MtFs and FtMs present differences with controls (Zubiaurre-Elorza et al., 2013).

Based on amputation studies and provisional data on the phantom limb phenomenon after penis or breast amputation in transsexuals, it was hypothesized that during embryological development the brain of transsexuals was hard-wired in a manner that was opposite to that of their natal sex (Ramachandran & McGeoch, 2007). No posterior study has verified this hypothesis nor have the preliminary data been published or shown by the authors.

Recently, a new strategy has been employed (Feusner et al., 2016). Homosexual/bisexual FtMs viewed photographs of their own body that were morphed by different degrees to bodies of other females or males and were instructed to rate “To what degree is this picture you?” FtMs differed from heterosexual male and female controls because they rated body images as more self-like when they were morphed to the sex congruent with their gender identity rather than to their natal sex.

Cerebral circuitry involved in body perception has been studied. The inferior parietal and premotor cortices play a role in perceptual judgment about body configuration; the insular lobes are involved in body awareness in general and the right insula in egocentric representation, self-recognition, and body ownership (Tsakiris, 2010). Circuitry and connectivity analyses have revealed the afferent and efferent connectivity of the insula, the somatosensorial, the temporo-parietal, and the premotor cortices. MRI and neuropsychological data favor a right hemispheric specificity for self-processing in general and for body ownership specifically. We have seen that MtFs differ from males in visuoperceptive regions such as the cuneus and calcarine region as well as in regions related with body perception and emotional experience of the body (insula) and reward value (medial orbitofrontal cortex; Fig. 2b). Moreover, some fascicles related to these regions are demasculinized (Fig. 3a). On the other hand, FtMs differ from males in the parietal and postcentral regions of the right hemisphere and have masculine fascicles related to these regions in the right frontal lobe (Figs. 2c, 3b). Thus, the available structural data show specific differences for MtFs and FtMs in cortical regions and fascicles involved in body perception.

Savic and Arver (2011) found that nonhomosexual MtFs have larger gray matter volume than male and female controls in the right parieto-temporal junction and the right inferior frontal and the insular cortices. As shown above, these regions are related to body self perception. The authors suggested that the experience of dissociation of the self from the body may be a result of failure to integrate complex somatosensory and memory processes in these regions. Future research should explore possible differences in the structural connectivity of these regions.

Differences have been detected in the neural network of body representation in transsexuals (Lin et al., 2014). Lin et al. investigated the regional changes in the degree of centrality in resting-state functional connectivity of the brain; the degree of centrality is an index of the functional importance of a node in a neural network. They hypothesized that three key regions of the body representation network (primary somatosensory cortex, parietal lobe, and insula) would show a higher degree of centrality in untreated transsexuals with respect to controls. Transsexuals do show a higher degree of centrality in the bilateral parietal lobe and the somatosensory cortex. However, their data analysis pooled the data from MtFs and FtMs. Although the findings of Lin et al. are indicative of specific connectivity features in transsexuals, they should be taken cautiously until separate analyses distinguishing between MtFs and FtMs, the onset of the GD, and sexual orientation can be presented.

Comment on the Brain of Nonhomosexual Transsexuals

As noted above, there is only one morphological study on untreated nonhomosexual transsexuals in the literature (Savic & Arver, 2011). This study and our proposed phenotypes for homosexual MtFs and FtMs could help us take the first steps in discerning between homosexual and nonhomosexual transsexuals. Homosexual MtFs are female-like in a series of sexually dimorphic behaviors, while nonhomosexual MtFs are not (Blanchard, 1989a, 1989b). It has also been hypothesized that the brain of homosexual and nonhomosexual MtFs would differ from that of males in different ways. In homosexual MtFs, the differences would involve sexually dimorphic structures and the nature of the differences would be a shift toward the female-typical patterns, while in nonhomosexual MtFs the differences themselves would not involve sexually dimorphic structures (Blanchard, 2008). Moreover, it was also suggested that “if there is any neuroanatomic intersexuality, it is in the homosexual group” (Blanchard, 2008).

Following this line of thought, Cantor (2011, 2012, but also see Italiano, 2012) has recently suggested that Blanchard’s predictions have been fulfilled in two independent structural neuroimaging studies. Specifically, Savic and Arver (2011) using VBM on the cortex of untreated nonhomosexual MtFs and another study using DTI in homosexual MtFs (Rametti et al., 2011b) illustrate the predictions. Cantor seems to be right. Nonhomosexual MtFs present differences with heterosexual males in structures that are not sexually dimorphic (Savic & Arver, 2011), while homosexual MtFs (as well as homosexual FtMs) show differences with respect to male and female controls in a series of brain fascicles (Rametti et al., 2011a, 2011b). If other VBM and CTh studies on the cortex of homosexual MtFs are added (Simon et al., 2013; Zubiaurre-Elorza et al., 2013), there is a more substantial number of untreated homosexual MtFs and FtMs that fulfill Blanchard’s prediction but still only one study on nonhomosexual MtFs; to fully confirm the hypothesis, more independent studies on nonhomosexual MtFs are needed. A much better verification of the hypothesis could be supplied by a specifically designed study including homosexual and nonhomosexual MtFs.

Finally, for Blanchard, MtF and FtM homosexual transsexuality is an extreme expression of homosexuality. He considered the following continuum: homosexual → gender dysphoric homosexual → transsexual homosexual (Blanchard, Clemmensen, & Steiner, 1987). Later, Blanchard also hypothesized that homosexual transsexuals should show differences in sexually dimorphic brain structures (Blanchard, 2008). Thus, from Blanchard’s view, there would be no brain differences between homosexual transsexuals and homosexual persons. This hypothesis has not been directly tested yet. However, there are two studies in the literature with respect to cortical thickness that, taken cautiously, may approach Blanchard’s hypothesis on the relationship between transsexuality and homosexuality.

The only study on the CTh of homosexual persons that do not present gender dysphoria is by the Savic group (Abé et al., 2014). If we compare this study with that of Zubiaurre-Elorza et al. (2013) on the CTh of homosexual MtFs, we see both studies report sex differences showing an F > M pattern in similar structures of the right hemisphere. But there is only one region, the pars triangularis, in which homosexuals and homosexual MtFs both present differences. However, these changes are in opposite directions. The pars triangularis of homosexual MtFs is thicker than in heterosexual male controls, while for homosexuals it is thinner than in heterosexual males. Thus, it seems that for transsexuals this region is feminized but demasculinized in homosexual individuals. Interestingly, in both studies, the affected pars triangularis is in the right hemisphere. Nevertheless, confirming Blanchard’s prediction still needs a specifically designed comparison of homosexual MtF, homosexual male, and heterosexual male and female people.