Or “It’s all in your head – no, really!”

It’s clear that a significant segment of human society has difficulty accepting that transsexuality is a real medical condition which is part of our inherited genetics. The common tactic of the blatant transphobe is to dismiss us as freaks, psychopaths, or even monsters deserving of involuntary institutionalism. The casual transphobe, or crafty one, will instead often use phrasing, like this copied from an online debate I participated in.

“Hey, I don’t care if someone thinks they’re Napoleon. What. Ever. But don’t expect me to salute them or call them Emperer[sic]. That would make me as crazy as they are. This is just common sense, people.”

Sadly, as seen in any political debate, “common sense” is a meaningless phrase loaded with contrived meaning, almost always uncommon and insensible. “We want common sense measures to keep dangerous weapons off our streets!” versus “Giving people the ability to defend themselves against criminals is just common sense!” With so much “common sense” out there, it’s amazing that anything ever goes wrong!

So let’s try to dispense with “common sense,” and my editorializing upon such, and look at the facts. I’m going to address the following points in order:

How the genitals and brain develop their respective gendering, and significant cases of brain and genital misalignment resulting from endogenous or exogenous chemicals.

Clues given to us from hereditary studies.

Karyotype aberrations from the normal XX and XY chromosomes.

Several significant differences from the average population which have been found in the brains of transsexuals.

Contrary research which indicates there may be either a limited or no difference between the brains of transsexuals and the general population.

Note: “Transsexual” is used somewhat synonymously with “transgender” in this article. The word “transsexual” will be the default term, as it typically is used in scientific literature, unless there is a specific need for the broader umbrella term “transgender.” Also note, “transwomen” refers to male-to-female transsexuals, and “transmen” refers to female-to-male transsexuals.

Brain Development

Gender identity was once thought of as being entirely a social construct, with most of our gender formation occurring between the ages of 1-4. (Bao, Gooren 2006) In the 21st century, the general thought is that gender identity is programmed at birth, although social factors can potentially overwhelm this programming. One tragic example is the “John-Joan-John” case, where a boy who lost his penis at 8 months was surgically turned into a girl, including the administration of estrogens and receiving psychological counseling. Although raised a girl all her life, she had the unshakeable feeling that she was in fact a boy. She transitioned back to male at age 14, and attempted to live as a male, but eventually, due to financial instability and a failing marriage, committed suicide. (Bao)

It’s common to hear the phrase “all babies start out female, and it’s only later that they become male,” and this is at least partially true. In fact, the influence of testosterone on a fetus has been described as a defeminization process, changing a fetus which was essentially predestined to be female into male. (Gooren, 2006) Testosterone production and the conversion of some testosterone to dihydrotestosterone between weeks 6 and 12 of pregnancy is critical for the initial development of male features, such as the penis, prostate gland, and scrotum. (Bao) In the absence of these male hormones, female genitalia develop instead. Brain development, however, does not occur in earnest until the second half of the pregnancy term, after the genitals have been developed, and the continued presence of male hormones results in a brain which has subtle, but critical physical differences from the female brain. (Bao)

The fact that the brain and the genitals develop at different times in the womb mean that a misalignment between the genitals and brain may develop, leading to either an intersex condition, or a transgender individual.

Example 1: Women with complete androgen insensitivity syndrome (CAIS) develop bodies which are almost entirely female, and they tend to be sexually oriented towards men – despite having an XY karyotype. (Bao, Gooren 2006) Often, there is no indication the child is anything but female until surgery or an x-ray reveals the presence of undescended testes. (Gooren, 2006)

Example 2: Either a 5α-reductase-2 or a 17β-hydroxy-steroid dehydrogenase-3 deficiency will prevent the formation of testosterone into dihydrotestosterone, which will result in an XY karyotype baby girl with a large clitoris. However, when puberty arrives the girl will discover to her alarm that her clitoris grows significantly, her testes descend, and she will begin to take on masculine features. (Bao, Gooren 2006) Even though children with these birth defects are raised as girls, about 60% will become heterosexual males. (Bao) A Brazilian study found that of 25 5α-reductase-2 affected babies who were raised as girls, 13 changed their gender identity to male after puberty. (Gooren, 2006) Another study found that about 50% of 17β-hydroxy-steroid dehydrogenase-3 affected babies changed their gender identity back to male at puberty. (Gooren, 2006) What these results indicate to us is that testosterone likely more directly impacts the organization of the fetal brain than dihydrotestosterone. (Bao)

Example 3: Boys with an XY karyotype who are born with a cloacal exstrophy (where they are either partly or completely missing a penis) are typically changed surgically into “girls” just after birth, and are given female hormone therapy and counseling. However, about half of these new girls later determine that they are really boys, and change their social gender when they become teenagers or adults. (Bao, Gooren 2006)

Example 4: Girls with an XX karyotype born with congenital adrenal hyperplasia (CAH) (meaning they were exposed to high levels of testosterone in the womb) tend to develop male social tendencies and male personality features. (Hines, Zucker) They tend to be described by their parents as “tomboys”, with a high energy level. (Gooren, 2006) CAH girls are 100-300 times as likely to be transsexual, compared to the general female population, and 1 in 20 have serious gender identity problems. (Bao) One study found that 37% of CAH girls classified themselves as either lesbian or bisexual, a number far greater than the general population. (Gooren, 2006)

Example 5: Phenobarbital or diphantoin administered to pregnant women as anticonvulsants can increase the chance of giving birth to a transsexual child.(Bao, Dessens) The belief, not proven conclusively at this juncture, is that these chemicals disrupt the influence of testosterone on the brain in the womb. (Bao, Swaab) In other cases, it’s believed that prenatal exposure to estrogens, progestins, and antiandrogenic chemicals could suppress endogenous testosterone production by interfering with the hypothalamic-pituitary-testicular axis. However, studies have focused largely on sexual preference as a result of this exposure, rather than gender identity, and in general these drugs were primarily only given to pregnant women between 1940-1970. (Gooren, 2006) There is some evidence that exposure to DDT could be responsible for increased polycystic ovary syndrome (PCOS) in women, increased idiopathic oligospermia (IO) in men, and increased transsexualism. Notably, transmen are found to often have PCOS, while transwomen often have IO. (Balen, Dorner) One study found transmen were 32.5% more likely to have endocrine dysfunction than XX karyotype women. (Futterweit)

Example 6: Kallmann’s Syndrome, a condition which occurs due to deficiency of gonadotropin-releasing hormone. The result can be an adult who has a loss of secondary sex characteristics. It is found much more frequently in genetic males than in genetic females, and male sufferers typically have what the medical literature describes as “eunuchoid growth,” with delayed or absent puberty, undeveloped infantile genitals, sparse body hair growth, a high-pitched voice, and other feminine features. Some of those with Kallmann’s Syndrome will become transsexual, although this is rare. (Meyenburg, 2001)

Even in these factual cases, questions remain about the connection between genetic and physical factors and gender identity. For example, why wouldn’t a preponderance of those with cloacal exstrophy feel they were boys? This likely attests either to the complexity of the physical processes involved, randomness in our development process, or the intense pressures social upbringing can exert upon both our gender and sexual attraction.

Other recent studies cast some question on what is more important in creating a feminized brain – the presence of two X chromosomes, or the presence of a Y chromosome and a sufficient level of testosterone. It’s a subtle argument, which essentially is trying to determine if hormones are the only differentiator between male and female brains, or whether there are other factors. One study which compared XX, XXY, and XY individuals came to the conclusion that having two X chromosomes is responsible for differences in the formation of the amount of gray matter in the cerebrum and precentral areas of the brain. However, the presence of testosterone appeared to be responsible for differences in the amygdala, parahippocampus, and occipital cortex. Thus, any condition which would reduce or interfere with the testosterone that the fetus was exposed to could result in an intersex or transgender brain. However, it is also possible that XXY individuals may have other compounding factors which can skew the data. (Lentini)

Heredity Studies

Transwomen who are sexually attracted to men have been found to be more likely to be the younger or youngest children in families with more brothers than sisters. (Bao) A study of 417 transwomen and 96 transmen found that transwomen had significantly more maternal aunts than uncles, while transmen showed no clear trends. Interestingly, this trend was strongest in lesbian transwomen, while an even stronger trend was seen for asexual transsexuals of both birth sexes, where they had more maternal uncles than aunts. (Green & Keverne) There is some speculation that this could be a result of a defect in the X chromosome from the mother, similar to fragile-X syndrome. Twin studies have shown a hereditary component for gender identity disorder (GID). (Swaab) One study of gender identity disorder in 314 twins found a heritable trait – and thus, implying strong genetic trait – as being 62% likely. (Coolidge) In some rare cases, two or more transsexuals have been born into a single family generation, (Green, Sabalis, Sadeghi) and in some cases transsexualism has been inherited from a transsexual parent. (Green)

Karyotype Aberrations

None of the cases above address profound karyotype aberrations, such as Klinefelter’s syndrome (47,XXY karyotype males, or 47,XXY/46,XY mosaics, or even the exceedingly rare 47,XXY/46,XX mosaicism), which can occur in 1 out of 1,000 male births. (Khandelwal) Other karyotype aberrations of note include 47,XYY males and 47,XXX females. In all of these cases the individual can develop gender identity disorder and become a transsexual (Khandelwal); indeed, this author personally knows individuals in this category who have become transsexuals.

Evidence for Physical Differences in the Transgender Brain

Despite the many profound genetic aberrations which can occur to create a transgender individual, most of us do not fall under any of the examples listed above. Here we must look to much more subtle evidence, and the majority of studies searching for a physical cause for transgender individuals have found physiological and genetic differences which can be tested and measured. And most of these differences are found in our brains.

This is my brain. Do you like it? I’m somewhat fond of it. This is a single MRI slice through the center of my brain which was done when the doctors were trying to diagnose my intersex hormone condition. It was suspected that I had a pituitary adenoma or tumor, but it turns out my brain is in absolutely perfect shape, excepting a pineal gland cyst of no real significance at this juncture.

For the record, it’s a very sobering thing to look at your own brain, especially when you flip through all the image “slices” on the DVD they give you. You get the impression that your brain went through a virtual deli counter meat slicer.

Before we look at the results of brain studies, there are some points of scientific fairness which need to be addressed. The first one is that all of the physical manifestations which are listed below are subtle effects. You will not see these on an X-ray, nor even an MRI without specifically looking for them. If the differences in the brains of transsexuals were significant and profound, we wouldn’t be faced with having to continually justify our existence and alleged “motivations” in the first place. The second thing to note is that the uncertainty values of many of these studies are quite high, because there is significant variation in the brains of individuals from person to person. Finally, we need to recognize that because we are “rare and beautiful creatures,” and so many of us are closeted and unwilling to participate in studies, many of these studies have only examined a very small sample sizes of transsexuals.

Keeping all of that in mind, let us look at the evidence.

XY karyotype men have about twice the volume and twice the number of neurons as XX karyotype women in two regions of the brain, called the BSTc and INAH3 regions. (Bao, Kruijver) An early study of cadaver brains found that transwomen have roughly the same numbers of neurons in these areas as XX women (Zhou), and this has been backed up by further non-invasive imaging studies. (Bao, Kruijver) A single transman who was tested was found to have an XY male number of neurons.(Bao, Kruijver) However, it should be noted that in the imaging study, the differences from person to person were somewhat wide-ranging, and the sample sizes were very small.

From Bao – note the similarity between female and MtF subjects – note “CAS” refers to the “castrated male” group.

MRI data from 24 transwomen who had not started hormone treatment revealed that while their overall grey matter appeared similar to that of XY karyotype males, they possessed a significantly larger amount of grey matter in the right putamen. In fact, the grey matter structure of the transwomen was much closer to those seen in XX karyotype female subjects. In short, while the brains of the transwomen resembled XY male brains in terms of grey matter, in one specific region their brains appeared to be “feminized.” (Luders)

A study of the white matter in the brains of 18 transmen, 24 XY karyotype males, and 19 XX karyotype females using diffusion tensor imaging (DTI) showed that the white matter structure of transmen was much closer to that of XY males than XX females. In fact, the white matter of their brain differed from the XY males only in a single region of the brain, whereas they differed from the XX women in three regions of the brain. None of the transmen had received hormone treatment at the time of the study. (Rametti, 2011) A follow-up study by the same researchers found that after the transmen had received hormone treatment, significant changes occurred in their brains, making them appear even more masculinized in certain regions which are associated with XY males. (Rametti, 2012)

From Rametti (2011) – note where F-toM subjects lie, right between female and male subjects, and identical to males in one region.

A positron emission tomography (PET) study showed that smelling androgens (male pheromones) caused transwomen to respond in the hypothalamus region of their brain in a manner similar to XX karyotype women. However, smelling estrogen-based pheromones also caused them to respond in the hypothalamus region in a manner similar to XY karyotype men. This combination of results suggests that transwomen occupy an “intermediate position with predominantly female features” in the way the hypothalamus reacted. (Berglund)

An MRI study of 22 transwomen and 28 transmen examined the shape of the corpus callosum in the brain at a specific cross-sectional plane, and compared this shape with that observed in 211 XY karyotype males and 211 XX karyotype females. Their results demonstrated that not only could the sex of the patient be determined with 74% accuracy from the MRI picture, but the shapes of the brains in the transsexuals strongly reflected their gender, and not their biological sex. (Yokota)

From Yokota – note the shape and skewing of the histograms – MTF subjects are closer to females than males, and FTM subjects are closer to males than females.

A recent study examined cortical thickness in the brain between 29 XY karyotype males, 23 XX karyotype females, 24 transmen, and 18 transwomen. None of the transsexual subjects had received any hormone treatment prior to the study. Using an MRI, the researchers found that the transwomen had more cortical thickness than the XY males in three regions of the brain. The transmen showed evidence of masculinization of their grey matter. In all transsexuals studied, the key differences from their biological sex were found in the right hemisphere. (Zubiaurre)

From Zubiaurre – note again where FtM subjects lie in the comparison.

Testing of a chemical produced in our bodies called “brain-derived neurotropic factor” (BDNF) in 45 transwomen found that when they were compared with 66 XY karyotype male control subjects, the transwomen had significantly lower levels of BDNF. However, this could be a result of higher stress levels and higher emotional trauma levels in the transsexual sampling. It should also be noted that no women control subjects were compared in this study. (Fontanari)

Genetic testing of 112 transwomen and 258 XY karyotype male control subjects found that the transwomen had significant differences in androgen receptor genes. The result of this difference could lead to less effective testosterone signaling, meaning that there would be significantly less “masculinization” of the brain in the womb. This would result in a brain which was much more feminized, leading to a female gender identity. (Hare)

An admittedly small study of 9 post-operative transwomen showed their brain activation was similar to women when viewing pictures showing erotic male images. (Oh) However, this study doesn’t so much address the root cause of the transsexuality as it shows that their sexual attraction towards men led to the same brain reaction as seen in heterosexual women.

Evidence Which May Indicate or Imply Physical Differences in the Transgender Brain

A 2013 study from Taiwan compared transsexuals with control subjects using two different assessments. In the first comparison, 41 transwomen were compared against 38 control subjects in a behavioral study to see how they would respond to pornographic short films. The results showed that transwomen overwhelmingly saw themselves in the role of their mental gender while watching the films. The second study was objective rather than subjective, and used functional MRI to compare the brains of 23 transwomen who had not been treated with hormones with 23 age-matched control subjects. The result was a significant difference in brain activity, primarily in the dorsal and pregenual ACC regions of the brain, between the transwomen and the controls. These regions of the brain are typically associated with processing feelings of social exclusion and emotional conflicts, so this may not indicate a difference in the brain due to gender identity differences, but rather a difference due to the negative social results of gender identity differences. (Ku, 2013)

From Ku – H-/TXs are transwomen, and fcCONs are controls.

Evidence Against Physical Differences in the Transgender Brain

In opposition to these studies, however, there are some studies which have found no significant differences between the brains of transsexuals and the population at large.

Early studies directly examining the corpus callosum in the brains of 20 transsexuals found no significant differences on a gross level between their brains and those of 40 control subjects. (Emory) However, The MRI technology which was employed was relatively new at the time of the study (1991).

A study of four sex-sensitive mental processes (rotation of an object, visualization of objects, perception, and verbal skills) found no significant differences between transwomen and XY karyotype males. However, analysis of the results actually showed biological sex only influenced rotation and visualization, and previous results showing XY versus XX differences in perception and verbalization were not shown. This could point to a flaw in the study, as other studies have shown significant differences. (Haraldsen)

Many studies have pointed to the difference between the length of the index finger and the ring finger being an indicator of androgen exposure before birth. In a “normal” XY karyotype male, the index finger is significantly shorter than the ring finger, which has led some to question whether transwomen with that same finger pattern have any significant physiological differences from XY males. However, as noted above gendering of the brain is not due to just simple androgen exposure, and studies have found the finger-length test to be poor, with a 60% overlap between XY men and XX women. (Gooren, 2006)

A study of 30 transwomen and 31 transmen found only two transwomen possessed a detectable DNA defect. (Hengstschläger) This study has been criticized for being too small and for not looking deep enough into the genome to find potentially subtle differences in genetics. However, a sample size of 61 transsexuals is at least average, if not larger than average, and the study otherwise seems sound.

Recently, there has been some focus on differentiating transsexual women who are attracted to men, versus those attracted to women. A criticism is that many of these brain studies do not account for these differences (e.g., Luders) and should do such, and some researchers claim that their studies of the brains of lesbian transwomen show no significant differences from male brains. (Savic) This has led to debate within the research community as to whether or not differentiation is even needed, with no clear resolution forthcoming. (e.g. Cantor, Italiano)

Some researchers feel that the evidence is intriguing, but too subtle and difficult to study or replicate, and therefore not conclusive enough to say that transsexuality is a brain structure-focused intersex condition. (Meyer-Bahlburg)

Summary

Taking the entire breadth of the findings uncovered by my research, it appears that there is more than sufficient evidence that transgender persons either have a serious hormonal-based birth defect, have been exposed to exogenous chemicals which have impacted their gender development in the womb, have a genetic karyotype which differs from the general population, or via some other process have a brain structure which is different than would be indicated by their chromosomes. While no single study presents proof beyond any shadow of a doubt or with metaphysical certainty, taken together they do present a preponderance of evidence such that one can say with confidence that transgender individuals have a congenital gene-based difference from cissexual individuals.

Una is a professional science researcher and part-time university professor. The reader is encouraged to perform their own follow-up and fact-checking with the references listed below. Unintentional bias may exist in this article, as the author is herself an intersex transsexual woman. No personal, commercial, or academic conflict of interest exists between the author and any authors or institutions cited as references.

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