Causes of transsexuality

Genetics

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. 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.

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.

Transsexuality among twins

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 non-identical twin pairs, there was only 1 of 38 (2.6%) pairs where both twins were trans. The significant percent of identical twin pairs where both twins are trans, and the virtual absence of dizygotic twins (raised in the same family at the same time, but not genetically identical) where both were trans, if both sets were raised in different families would provide evidence that transgender identity is significantly influenced by genetics.

Brain structure

Several studies have found a correlation between gender identity and brain structure. 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), male-to-female trans women had a female-normal BSTc size (like cisgender women) and female-to-male trans men had a male-normal size. While the transsexuals studied had taken hormones, this was accounted for by including 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.

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 who matched up with the female neuron counts nonetheless.

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.

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. Dick Swaab (2004) concurs.

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.

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 men than women, but there was a significantly larger volume of gray matter in the right putamen compared to men. Like earlier studies, it concluded that transsexuality was associated with a distinct cerebral pattern. (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."

Hulshoff Pol et al. (2006) studied the gross brain volume of 8 male-to-female transsexuals and in 6 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."

Brain-based research has repeatedly shown 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. 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).

Similar brain structure differences have been noted between gay and heterosexual men, and between lesbian and heterosexual women. Studies have also found that circumstance and repeated activities such as meditation modify brain structures in a process called brain plasticity or neuroplasticity. In May 2014, the Proceedings of the National Academy of Sciences reported that parenting "rewires the male brain" for fathers.

Androphilic male-to-female transsexuals

Studies have shown that androphilic male-to-female transsexuals (sometimes called homosexual MtF 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.

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.

Gynephilic male-to-female transsexuals

Gynephilic male-to-female transsexuals also show differences in the brain from non-transsexuals, in a pattern intermediate between male or female, or more female than male. 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."

These 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).

Berglund et al. (2008) tested the response of gynephilic MtF transsexuals to two 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 sexuality, 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. Male control groups (gynephilic) 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. 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.

Gynephilic female-to-male transsexuals

Another team of neuroscientists, led by Nawata in Japan, used a technique called single-photon emission computed tomography (SPECT) compare the regional cerebral blood flow (rCBF) of 11 female-to-male transsexuals (attracted to women) with that of 9 cis females (attracted to men). 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 female-to-male 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.

Phantom limb syndrome

Phantom limb syndrome is a common, often painful experience after the loss of an external organ. Ramachandran (2008) found that while nearly two thirds of non-transsexual males who have a penis surgically removed experience the sensation of a phantom penis, only one third of MtF transsexuals do so after sex reassignment surgery. However, this study overlooks differences between an amputation, where nerves connecting the penis and brain are severed, and reassignment surgery, where some of the penis and scrotum may be reused to create a vaginal canal, labia and a clitoris. In this case, some nerves connecting the genitalia to the brain remain intact. Two thirds of FtM transsexuals reported the sensation of a phantom penis from childhood onwards, complete with phantom erections and other phenomena.

Prenatal androgen exposure

Prenatal androgen exposure, the lack thereof, or poor sensitivity to prenatal androgens are commonly cited mechanisms to explain the above discoveries. Schneider, Pickel, and Stalla (2006) found a correlation between digit ratio (a generally accepted marker for prenatal androgen exposure) and male-to-female transsexuality. MtF transsexuals were found to have a higher digit ratio than control males, but one that was comparable to control females.

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, in controversial prenatal hormone treatment and postnatal surgical interventions. 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, and at least 5.2% of these individuals develop serious gender dysphoria.

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.

Rearing

For many years, people such as psychiatrist and sexologist David Oliver Cauldwell and Harry Benjamin argued that transsexuality was a psychological/emotional disorder caused by psychological and environmental factors and personality conflicts. The failure of an attempt to raise David Reimer from infancy through adolescence as a girl after his genitals were accidentally mutilated is cited as disproving this theory that gender identity is determined by parenting. However, no studies have been able to demonstrate this at a large scale, in part due to widespread agreement among scholars that the Reimer study's methodology was unethical. Reimer's case is used by organizations such as The Intersex Society of North America to caution against needlessly modifying the genitals of unconsenting minors.

Blanchard's theories about sexuality

Ray Blanchard has developed a taxonomy of male-to-female transsexualism built upon the work of his colleague Kurt Freund, which assumes that trans women have one of two motivations for transition. 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 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. 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. Many authorities, including some supporters of the theory, criticize Blanchard's choice of wording as confusing or degrading. Transsexuals themselves overwhelming reject the theory, with evolutionary biologist and trans woman Julia Serano writing 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." Blanchard's ideas about trans women have also been rejected by the World Professional Association for Transgender Health (WPATH), the largest association of medical professionals who provides care for transgender people, as lacking empirical evidence and for stigmatizing behavior instead of focusing on treating distress.

The DSM-5 Sexual and Gender Identity Disorders workgroup, of which Blanchard is a member, has said:

In contemporary clinical practice, sexual orientation per se plays only a minor role in treatment protocols or decisions. Also, changes as to the preferred gender of sex partner occur during or after treatment (DeCuypere, Janes, & Rubens, 2005; Lawrence, 2005; Schroder & Carroll, 1999). It can be difficult to assess sexual orientation in individuals with a GI diagnosis, as they preoperatively might give incorrect information in order to be approved for hormonal and surgical treatment (Lawrence, 1999). Because sexual orientation subtyping is of interest to researchers in the field, it is recommended that reference to it be addressed in the text, but not as a specifier. It should also be assessed as a dimensional construct.