Causes of transsexuality

A 2008 study compared 112 male-to-female transsexuals (both androphilic and gynephilic), mostly already undergoing hormone treatment, with 258 cisgender male controls. Male-to-female transsexuals were more likely than cisgender males to have a longer version of a receptor gene (longer repetitions of the gene) for the sex hormone androgen or testosterone, which reduced its effectiveness at binding testosterone.[6] The androgen receptor (NR3C4) is activated by the binding of testosterone or dihydrotestosterone, where it plays a critical role in the forming of primary and secondary male sex characteristics. The research suggests reduced androgen and androgen signaling contributes to the female gender identity of male-to-female transsexuals. The authors say that a decrease in testosterone levels in the brain during development might prevent complete masculinization of the brain in male-to-female transsexuals and thereby cause a more feminized brain and a female gender identity.[6][7]

A variant genotype for a gene called CYP17, which acts on the sex hormones pregnenolone and progesterone, has been found to be linked to female-to-male transsexuality but not MtF transsexuality. Most notably, the FtM subjects not only had the variant genotype more frequently, but had an allele distribution equivalent to male controls, unlike the female controls. The paper concluded that the loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexuality.[8]

In 2013, a twin study combined a survey of pairs of twins where one or both had undergone, or had plans and medical approval to undergo, gender transition, with a literature review of published reports of transgender twins. The study found that one third of identical twin pairs in the sample were both transgender: 13 of 39 (33%) monozygotic or identical pairs of assigned males and 8 of 35 (22.8%) pairs of assigned females. Among dizygotic or genetically non-identical twin pairs, there was only 1 of 38 (2.6%) pairs where both twins were trans.[5] The significant percent of identical twin pairs in which both twins are trans and the virtual absence of dizygotic twins (raised in the same family at the same time) in which both were trans would provide evidence that transgender identity is significantly influenced by genetics if both sets were raised in different families.[5]

Several studies have found a correlation between gender identity and brain structure.[9] A first-of-its-kind study by Zhou et al. (1995) found that in a region of the brain called the bed nucleus of the stria terminalis (BSTc), a region which is known for sex and anxiety responses (and which is affected by prenatal androgens),[10] cadavers of six persons who were described as having been male-to-female transsexual or transgender persons in life had female-normal BSTc size, similar to the study's cadavers of cisgender women. While those identified as transsexual had taken hormones, this was accounted for by including cadavers of non-transsexual male and female controls who, for a variety of medical reasons, had experienced hormone reversal. The controls still had sizes typical for their gender. No relationship to sexual orientation was found.[11]

In a follow-up study, Kruijver et al. (2000) looked at the number of neurons in BSTc instead of volumes. They found the same results as Zhou et al. (1995), but with even more dramatic differences. One MtF subject, who had never gone on hormones, was also included and matched up with the female neuron counts nonetheless.[12]

In 2002, a follow-up study by Chung et al. found that significant sexual dimorphism (variation between sexes) in BSTc did not become established until adulthood. Chung et al. theorized that either changes in fetal hormone levels produce changes in BSTc synaptic density, neuronal activity, or neurochemical content which later lead to size and neuron count changes in BSTc, or that the size of BSTc is affected by the generation of a gender identity inconsistent with one's assigned sex.[13]

It has been suggested that the BSTc differences may be due to the effects of hormone replacement therapy. It has also been suggested that because pedophilic offenders have also been found to have a reduced BSTc, a feminine BSTc may be a marker for paraphilias rather than transsexuality.[3]

In a review of the evidence in 2006, Gooren confirmed the earlier research as supporting the concept of transsexuality as a sexual differentiation disorder of the sex dimorphic brain.[14] Dick Swaab (2004) concurs.[15]

In 2008, a new region with properties similar to that of BSTc in regards to transsexuality was found by Garcia-Falgueras and Swaab: the interstitial nucleus of the anterior hypothalamus (INAH3), part of the hypothalamic uncinate nucleus. The same method of controlling for hormone usage was used as in Zhou et al. (1995) and Kruijver et al. (2000). The differences were even more pronounced than with BSTc; control males averaged 1.9 times the volume and 2.3 times the neurons as control females, yet once again, regardless of hormone exposure, MtF transsexuals lay within the female range and the FtM transsexual within the male range.[16]

A 2009 MRI study by Luders et al. of 24 MtF transsexuals not yet treated with cross-sex hormones found that regional gray matter concentrations were more similar to those of cisgender men than to those of cisgender women, but there was a significantly larger volume of gray matter in the right putamen compared to cisgender men. Like earlier studies, it concluded that transsexuality was associated with a distinct cerebral pattern.[17] (MRI allows easier study of larger brain structures, but independent nuclei are not visible due to lack of contrast between different neurological tissue types, hence other studies on e.g. BSTc were done by dissecting brains post-mortem.)

An additional feature was studied in a group of FtM transsexuals who had not yet received cross-sex hormones: fractional anisotropy values for white matter in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Rametti et al. (2010) discovered that, "Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract."[18]

Hulshoff Pol et al. (2006) studied the gross brain volume of 8 male-to-female transsexuals and in six female-to-male transsexuals undergoing hormone treatment. They found that hormones changed the sizes of the hypothalamus in a gender consistent manner: treatment with male hormones shifted the hypothalamus towards the male direction in the same way as in male controls, and treatment with female hormones shifted the hypothalamus towards the female direction in the same way as female controls. They concluded: "The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain."[19]

Some brain-based research has indicated that female-to-male transsexuals have several male-like characteristics in neuroanatomy. In 2010, a team of neuroscientists compared 18 female-to-male transsexuals with 24 male and 19 female gynephilic controls, using an MRI technique called diffusion tensor imaging or DTI.[18] DTI is a specialized technique for visualizing white matter of the brain, and white matter structure is one of the differences in neuroanatomy between men and women. The study found that the white matter pattern in female-to-male transsexuals was shifted in the direction of biological males, even before the female-to-male transsexuals started taking male hormones (which can also modify brain structure).

A 2016 review agreed with the other reviews when considering androphilic trans women and gynephilic trans men. In addition, it found support for the predictions of Blanchard's transsexualism typology that androphilic and non-androphilic trans women have different brain phenotypes. It reported that hormone treatment may have large effects on the brain, and that cortical thickness, which is generally thicker in cisgender women's brains than in cisgender men's brains, may also be thicker in trans women's brains, but is present in a different location to cisgender women's brains.[3] It also reported a lack of evidence indicating that the brain structure of trans men differs from their assigned sex.[3]

Studies have shown that androphilic male-to-female transsexuals show a shift towards the female direction in brain anatomy. In 2009, a German team of radiologists led by Gizewski compared 12 androphilic transsexuals with 12 cisgender males and 12 cisgender females. Using functional magnetic resonance imaging (fMRI), they found that when shown erotica, the cisgender men responded in several brain regions that the cisgender women did not, and that the sample of androphilic transsexuals was shifted towards the female direction in brain responses.[20]

In another study, Rametti and colleagues used diffusion tensor imaging (DTI) to compare 18 androphilic male-to-female transsexuals with 19 gynephilic males and 19 androphilic cisgender females. The androphilic transsexuals differed from both control groups in multiple brain areas, including the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract. The study authors concluded that androphilic transsexuals were halfway between the patterns exhibited by male and female controls.[21]

A 2016 review reported that early-onset androphilic transgender women have a brain structure similar to cisgender women's and unlike cisgender men's.[3]

While MRI taken on gynephilic male-to-female transsexuals have likewise shown differences in the brain from non-transsexuals, no feminization of the brain's structure have, however, been identified.[3] Researchers of the Karolinska Institute of Stockholm used MRI to compare 24 gynephilic male-to-female transsexuals with 24 cisgender male and 24 cisgender female controls. None of the study participants were on hormone treatment. The researchers found sex-typical differentiation between the MtF transsexuals and cisgender males, and the cisgender females; but the gynephilic transsexuals "displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus".

The researchers concluded that:

Contrary to the primary hypothesis, no sex-atypical features with signs of 'feminization' were detected in the transsexual group ... The present study does not support the dogma that [male-to-female transsexuals] have atypical sex dimorphism in the brain but confirms the previously reported sex differences. The observed differences between MtF-TR and controls raise the question as to whether gender dysphoria may be associated with changes in multiple structures and involve a network (rather than a single nodal area).[22]

Berglund et al. (2008) tested the response of gynephilic MtF transsexuals to two steroids hypothesized to be sex pheromones: the progestin-like 4,16-androstadien-3-one (AND) and the estrogen-like 1,3,5(10),16-tetraen-3-ol (EST). Despite the difference in sexual orientation, the MtFs' hypothalamic networks activated in response to the AND pheromone, like the androphilic female control groups. Both groups experienced amygdala activation in response to EST. Gynephilic male control groups experienced hypothalamic activation in response to EST. However, the MtF subjects also experienced limited hypothalamic activation to EST. The researchers concluded that in terms of pheromone activation, MtFs occupy an intermediate position with predominantly female features.[23] The MtF transsexual subjects had not undergone any hormonal treatment at the time of the study, according to their own declaration beforehand, and confirmed by repeated tests of hormonal levels.[23]

A 2016 review reported that gynephilic trans women differ from both cisgender male and female controls in non-dimorphic brain areas.[3]

Fewer studies have been performed on the brain structure of transgender men. A team of neuroscientists, led by Nawata in Japan, used a technique called single-photon emission computed tomography (SPECT) to compare the regional cerebral blood flow (rCBF) of 11 gynephilic FtM transsexuals with that of 9 androphilic cis females. Although the study did not include a sample of biological males so that a conclusion of "male shift" could be made, the study did reveal that the gynephilic FtM transsexuals showed significant decrease in blood flow in the left anterior cingulate cortex and a significant increase in the right insula, two brain regions known to respond during sexual arousal.[24]

Prenatal androgen exposure, the lack thereof, or poor sensitivity to prenatal androgens are commonly cited mechanisms to explain the above discoveries. To test this, studies have examined the differences between transsexuals and cisgender individuals in digit ratio (a generally accepted marker for prenatal androgen exposure). A meta-analysis concluded that the effect sizes for this association were small or nonexistent.[25]

Congenital adrenal hyperplasia in persons with XX sex chromosomes results in what is considered to be excess exposure to prenatal androgens, resulting in masculinization of the genitalia and, typically, controversial prenatal hormone treatment[26] and postnatal surgical interventions.[27] Individuals with CAH are usually raised as girls and tend to have similar cognitive abilities to the typical female, including spatial ability, verbal ability, language lateralization, handedness and aggression. Research has shown that people with CAH and XX chromosomes will be more likely to be same sex attracted,[26] and at least 5.2% of these individuals develop serious gender dysphoria.[28]

In males with 5-alpha-reductase deficiency, conversion of testosterone to dihydrotestosterone is disrupted, decreasing the masculinization of genitalia. Individuals with this condition are typically raised as females due to their feminine appearance at a young age. However, more than half of males with this condition raised as females become males later in their life. Scientists speculate that the definition of masculine characteristics during puberty and the increased social status afforded to men are two possible motivations for a female-to-male transition.[28]

Ray Blanchard has developed a taxonomy of male-to-female transsexualism[39] built upon the work of his colleague Kurt Freund,[40] which assumes that trans women have one of two motivations for transition.[41][42][43] Blanchard theorizes that "homosexual transsexuals" transition because they are attracted to men, and characterizes them as displaying overt and obvious femininity since childhood; he then characterizes "non-homosexual transsexuals" as transitioning because they are autogynephilic (sexually aroused by the thought or image of themselves as a woman), and as being either attracted to women, attracted to both women and men, or asexual.

The theory has gained support from J. Michael Bailey, Anne Lawrence, James Cantor, and others who argue that there are significant differences between the two groups, including sexuality, age of transition, ethnicity, IQ, fetishism, and quality of adjustment.[44][45][46][47][48] However, the theory has been criticized in papers from Veale, Nuttbrock, Moser, and others who argue that it is poorly representative of MtF transsexuals and non-instructive, and that the experiments behind it are poorly controlled and/or contradicted by other data.[49][50][51][52] Many authorities, including some supporters of the theory, criticize Blanchard's choice of wording as confusing or degrading. Lynn Conway, Andrea James, and Deidre McClosky attacked Bailey's reputation following the release of The Man Who Would Be Queen.[53] Evolutionary biologist and trans woman Julia Serano wrote that "Blanchard's controversial theory is built upon a number of incorrect and unfounded assumptions, and there are many methodological flaws in the data he offers to support it."[54] The World Professional Association for Transgender Health (WPATH) argued against including Blanchard's typology in the DSM, stating that there was no scientific consensus on the theory, and that there was a lack of longitudinal studies on the development of transvestic fetishism.[55]

Autogynephilia, a propensity to be aroused by the thought of being a woman, has been proposed as an etiology of male-to-female transsexuality.[39] Autogynephilia is common among late-onset transsexuals.[56] A study on autogynephilic men found that they were more gender dysphoric than non-autogynephilic men.[57]

Michael Bailey speculated that autogynephilia may be genetic.[58]