This paper attempts to demonstrate that there are significant natural in-born sex differences found between the brains of those called transsexual people and others. It does so by showing the differences are due to normal genetic, hormonal and environmental forces that lead eventually to differences in the transsexual person’s brain. This development brings with it feelings of dysphoria regarding one’s gender identity. It is such feelings that lead to a desire for sex/gender change. These brain differences are sufficient enough to conclude that persons with a transsexual condition are intersexed. Simultaneously it is recognized that many intersexed persons will switch from their assigned gender, yet many will not.
Transsexual people are persons now also commonly referred to as trans persons or transgender persons. Those not transgender are commonly referred to as cisgender individuals. In an attempt to explain themselves trans persons often say they are convinced that they were born “in the wrong body.” They believe they have the anatomy of one sex but identity and the emotional awareness of the opposite sex. Transsexual persons are so convinced of this feeling that they desire to forego any advantages they think associated with their birth sex and seek transition to their opposite sex. And many are willing to attain the goal of transfer even at great expense financially, emotionally and socially as evidenced by divorce, separation from friends and family, and other such losses (https://www.quora.com/topic/Gender-Dysphoria; https://www.quora.com/topic/Transsexuality-1). The natural question arises – how does this feeling come about, what causes it?
The initial factor in the development of transsexualism involves genetics. Coolidge, Theda and Young, in 2002, reported, finding a strong heritable component to the condition they called Gender Identity Disorder (GID) symptomatology (Coolidge, Theda, & Young, 2002). With this they implied that gender identity was much less a matter of choice and much more a natural matter of biology. In 2013 a large study among trans persons found one third of monozygotic (identical) male twins, and approximately one quarter of female monozygotic twins, were concordant in transitioning; essentially no dizygotic (familial) twins were concordant in transitioning (Diamond, 2013). And in 2014 it was reported that concordance in transition had occurred even among a trans twin pair that were reared and lived apart (Segal & Diamond, 2014). In sum these findings support a basic biological underpinning of the trans condition.
Another feature of transsexual development needs understanding. This too points to its natural biological nature. It is known that the genitals and brain develop at different times. The genitals develop early prenatally during the first 6 – 12th week and they may develop in masculine or feminine form. If the genitals develop under the influence of the androgen testosterone they are masculinized. If they are not, female genitals develop. In comparison, the brain, it is believed, develops during the latter period of pregnancy and also is subject to the influence of androgen. If there is significant androgen present at that time there will be brain masculinization, if not, there will be brain feminization. It thus is clear that the brain and genitals can develop independently and under different forces (Bao & Swaab, 2011; Savik, Garcia-Falguera, & Swaab, 2010). As Reiner has said “The etiology of gender identity may be neither obvious nor easily conceptualized. Yet what is obvious is that the presence of androgen is critical. It is the determining factor in the development of ... behavioral dimorphism in humans—genital structure, ... male-typical behaviors, masculinization of the brain …“ (Reiner, 2002).
Thus, transsexuality could develop with the genitals indicating one sex while the brain indicates the other. In cases of ambiguous genitalia the degree of masculinization of the brain may differ from that of the genitals. A strict dichotomy between male and female may not occur; the shift between the sexes/genders may be partial and the individual left with feeling somewhat both male and female. This same individual might also feel female or male under different circumstances or at different times.
It is appropriate to state some generally accepted definitions. In general male and female maintaintheir usual meanings. A male has within the nucleus of each of his cells 22 pairs of thread-like structures called chromosomes. These particular chromosomes are called autosomes in recognition of a common appearance. The male also possesses a 23rd pair of chromosomes distinguished as sex chromosomes. These consist of a relatively uniform X appearing chromosome and a much smaller Y chromosome. The typical male also has two testicles, a penis, prostate and other usual features of male reproductive anatomy. A female, in contrast, has within her cells 22 pairs of autosomes and a 23rd pair of sex chromosomes with two X chromosomes. The typical female also has a vagina, two ovaries, a clitoris, uterus, oviducts and other features of female reproductive anatomy. Intersexed persons have, in the same body, both male and female biological characteristics that are typically found only separately in each sex. Often a person’s sex is determined by reference to that person’s chromosomal status with XY indicating male and XX indicating female. However, intersex features with their many conditions, often confound this.
Those with transsexual characteristics are defined and classified in different ways. Basically, they are those individuals who aspire to change their sex from male to female or female to male and all want to be so accepted in the gender they select; going from man to woman or woman to man. Typically, such persons are said to be dysphoric in regard to their gender; a condition that used to be known as Gender Identity Disorder (GID) but is currently known as Gender Dysphoria (DSM-V, 2015). This gender dysphoria refers to the impression that trans persons have that they live with a disturbing and troubling feeling of “living in the wrong body.” Despite being assigned male at birth because of their male genitalia they think they are female and should live socially as girls or woman. If they were assigned female at birth because of their female genitalia they think they should be male and socially live as boys or men. Inherently they believe the easiest way for them to solve their dilemma is to change their sexual characteristics. While it is obvious that, in general, males can live socially as girls or women, and females can live socially as boys or men, this is not without a heavy cost. Many think it is easier and more appropriate to have what has been called sex-reassignment surgery (SRS), which they prefer to consider genital confirmation surgery or genital reconstruction surgery. Such surgery had historically been, in many countries, a requirement for legal sex/gender change recognition. Such restrictions are increasingly being removed in many jurisdictions.
Those who did change from male-to-female were commonly designated as MtF, those who switched female-to-male were designated FtM. As a group they had historically been identified as having Harry Benjamin syndrome; named after the physician that first popularized the condition (Benjamin, 1966). They were considered as Women Born Transsexual (WBT) or Men Born Transsexual (MBT). Today the terms have been simplified so that the common terms used are trans women or trans men1.
In 2006 a consortium of physicians met to consider the evaluation and treatment of the many intersex varieties and different associated nomenclature such as hermaphrodite and pseudohermaphrodite. They agreedto designate intersex conditions as Disorders of Sex Development (DSD) (Hughes, Houk, Ahmed, & Lee, 2006)2.
While there are many varieties of intersex conditions, two basic types are considered. The first type, usually recognized as ambiguous at birth, is due to the infant showing no clear distinction between male and female, boy and girl. A second type of individual has typical-looking genitals but has internal intersexed features that are not apparent. These are occult intersex conditions. A person with an occult condition might, for instance, be born with both one ovary and one testis, or a gonad with combined ovarian and testicular features.
One common genetic intersex condition where the syndrome is not recognized at birth is the so-called Klinefelter syndrome (KS). Such persons have 23 pairs of typical autosomes with an additional set of sex chromosomes consisting of two or more X chromosomes and one or more Y chromosome. It is the complement of sex chromosomes that are unusual in having a variant number of Xs or Ys, e.g., XXY, XXXYY, XXYY, etc. The most common form is known as 47XXY. This condition is not usually recognized at birth because, at that time, the genitals look acceptably male and that is the way the child is generally raised. This can lead to problems, however, because persons with KS occasionally wished they were treated as girls. And typically those with the 47XXY condition, or one of its variants, develop female type breasts at puberty and come to live as women. Another common intersex situation occurs when a person has both prominent breasts simultaneously with male XY sex chromosomes, hidden testes and a vagina. This is the complete Androgen Insensitivity Syndrome (cAIS). This condition also is usually not recognized at birth because the person looks like a typical female infant to be raised as a girl.
The most common intersex variety is called congenital adrenal hyperplasia (CAH). These individuals have XX sex chromosomes, ovaries, and a hypertrophied clitoris that looks like a small penis. This condition is a natural result of an adrenal problem that results in excess androgen production and subsequent masculinization both of the body and behavior.
Less common are conditions in which persons appear to be female at birth and are raised as girls but after puberty develop as males. These are conditions where the person, congenitally, lacks crucial testosterone modifying enzymes but produces them at puberty. And when these enzymes come available they convert testosterone to the androgen dihydrotestosterone needed to masculinize the genitals. These conditions are distinguished in name by the deficiency of the enzyme involved, either 5-alpha reductase (5-alpha) or 17-beta-hydroxysteroid dehydrogenase (17-beta).
The 5-alpha condition is known to be prevalent in the Dominican Republic and the 17-beta condition relatively common among Arab populations in the Middle East. As genetic conditions they persist in groups that intermarry.
Even less common are mosaic situations in which the same individual possesses both XX and XY cell types. Such a person might have an arm considered male because its cells are all XY while the same person’s leg might be considered female because its cells are all XX.
The intersex condition might manifest by differences in several of these organs or functions simultaneously, e.g., by differences in the nature of the chromosomes, gonads, genitals, or elsewhere. Since most intersex phenomena are occult, the majority of individuals with such are often unaware of their condition. For trans persons it is the brain that is intersexed in a non-apparent way.
How has the intersexuality of the transsexual brain been revealed? Early findings of sex difference were reported in the rat brain by Gorski et al. in 1978 (Gorski, Gordon, Shrayne, & Southam, 1978 ). They termed this area with the sex difference the medial preoptic nucleus (MPON). This was followed some years later by an analogous report for the human brain that the anterior commissure and massa intermedia were found sexually different. The search for sex differences in the brain became an active topic for research.
Neuroanatomical sex differences were observed in the midsagittal area of both the anterior commissure and the massa intermedia in humans. This analysis was from postmortem tissue from 100 age-matched adult males and females. While not present in all individuals, when present the anterior commissure, was an average of 12%, larger in females than in males and the massa intermedia, was an average of 53% larger in females than in males. These sex differences were found even though the brains of males were larger than those of females. Previously, these investigators had also found differences in the shape of the splenium (more bulbous) of the corpus callosum but not in the area covered (Allen & Gorski, 1991).
This same laboratory team identified other sexually dimorphic cell groups in the preoptic area of the human hypothalamus (PO-AHA) and collectively termed them the Interstitial Nucleus of the Hypothalamus with four subregions named INAH 1, 2, 3 and 4 (Allen, Hines, Shryne, & Gorski, 1989). Of these, the volume of INAH-3 was found almost three times (2.8x) as large in men as in women, and contained more than twice as many cells. Between the ages of 10 and 93 years, the nucleus decreases greatly in volume and in cell number. It had been suggested that this region was related to sexual orientation (LeVay, 1991). It is located within an area that is essential for gonadotropin release and sexual behavior in mammals. Another cell group (INAH-2) was twice as large in the male brain, but also appeared to be related in women to circulating steroid hormone levels. Since the preoptic-anterior hypothalamic area influences gonadotropin secretion, maternal behavior, and sexual behavior in several mammalian species, these results suggest that functional sex differences in the hypothalamus are related to significant sex differences in neural structure (Allen et al., 1989).
As with the Allen et al. 1989 findings, Hofman and Swaab also researched the comparable area in the human. They reported the sexually dimorphic nucleus of the preoptic anterior region of the hypothalamus (SDN-POA) in the human was markedly sexually dimorphic in volume, number of cells contained and in its structural organization. They reported finding that the volume of a putative homologue of the area originally reported for the rat brain by Gorski et al. as sexually dimorphic, was also sexually dimorphic in the adult human hypothalamus. It was more than twice as large in men as in women and contained about twice as many cells (Hofman & Swaab, 1989). Among the most significant brain differences found were those of Zhou and colleagues (Zhou, Hofman, Gooren, & Swaab, 1995). They reported finding that in males the central division of the bed nucleus of the stria terminalis (BSTc) was significantly larger than in females.
Now consider neuroanatomical features found in the brains of transsexual peoples. In 1995 Zhou et al. were the first to report finding a female brain structure in genetically male trans persons. They hypothesized these findings supported the theory that gender identity develops as a result of a normal interaction between the developing brain and sex hormones (Zhou, M. A. Hofman, Gooren, & Swaab, 1995). The area implicated was the bed nucleus of the stria terminalis (BSTc) of the hypothalamus that is sexually dimorphic in size and number of cells contained. Kruijver et al. subsequently expanded upon this finding. They found the number of neurons in the BSTc of trans women was similar to that of the females among cisgender women. In contrast, the neuron number of a FtM transsexual was found to be in the male range (Kruijver et al., 2000). This work supports the paradigm that, for transsexual persons, sexual differentiation of the brain and genitals may go in opposite directions and points to a neurobiological basis of transsexualism and the accompanying gender dysphoria.
Subsequent studies continued to substantiate these findings. Garcia-Falgueras and Swaab in 2008, using three different staining techniques, reported finding that INAH3 volume and number of neurons in the brains of those who went male-to-female (trans women) is similar to that of control females (Garcia-Falguera & Swaab, 2008). They proposed that the sex reversal of the INAH3 in trans persons is at least partly a marker of an early atypical sexual differentiation of the brain and that the changes in INAH3 and the BSTc may belong to a complex network that may structurally and functionally be related to gender identity.
Others continued this line of research. Bao & Swaab reviewed all sorts of potential influence on the sexual behavior of the developing child and found little evidence the exhibited sex differences were due to rearing (Bao & Swaab, 2011). Others did find, however, in regard to play behaviors and personality characteristics a strong influence of prenatal androgen (Mathews, Fane, Conway, Brook, & Hines, 2009; Nordenstrom, Servin, Bohlin, Larsson, & Wedell, 2002).
Work from other groups also found significant sex differences relative to trans persons that followed the proposal that a testosterone surge masculinizes the fetal brain and the absence of such a surge results in a feminine one. Gizewski et al., using fMRI, tested the cerebral activation patterns of trans women during their viewing of erotic film clips. The responses of these trans persons were more like cisfemale than cismale controls (Gizewski et al., 2009). Simon et al., using a neural-imaging technique called voxel based morphometry (VBM) measured brain components from both trans women and trans men. This VBM is a procedure using statistical methods of analysis that allows one area to be compared with another. They found many brain areas in which the gray matter structure differed from that of controls, e.g. the cerebellum, the left angular gyrus and left inferior parietal lobe. They concluded that structural brain differences exist between the brains of trans persons and control subjects dependent upon the gender expressed by the trans persons (Simon, Kozak, & Simon, 2013). The comparison agreed more with the gender expressed contemporarily than the genitals present at birth.
Transsexual people were found to have sex differences in the corpus callosum, the largest white tract in the brain. While measures of this structure have, over the years been controversial, these current authors, using Fourier descriptors of callosal contours reported finding the value of their measures for those who had gender dysphoria more strongly reflected their mental sex of gender, than their genital sex. Yokota, Kawamura, and Kameya claim the differences large enough to use as objective measures for clinical diagnosis (Yokota, Kawamura, & Kameya, 2005).
Giuseppina Rametti et al., using diffusion tensor imaging, also studied the white matter structure in the brains of trans persons. They concluded that the white matter microstructure pattern in untreated trans men is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females) (Rametti, Carrillo, Gómez-Gil, & Junque C, 2011).
Thickness in the cortex of the brain of trans persons has also been found significantly different. Zubiarre-Elorza et al. showed that trans men showed a subcortical brain masculinization, while the brains of trans women showed feminization particularly in regions of the right hemisphere (Zubiarre-Elorza et al., 2013). Luders et al. in 2012 also found regions of cortical thickness that differed in the brains of transsexual persons. Their results revealed thicker cortices in the brains of trans women, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus). These findings provide further evidence that brain anatomy is associated with gender identity, where measures in trans women appear to be shifted away from gender-congruent men (Luders et al., 2012).
One last comment here is appropriate. Very recent research has reported that kisspeptin, a peptide crucial to reproduction by stimulating GnRH, has been shown to exhibit sex-reversal in persons who transitioned from male to female. This was considered to possibly reflect, at least partially, an atypical brain sexual differentiation associated with transsexualism (Taziaux et al., 2016).
Supporting these findings are many other reports documenting human male—female sex differences that show the brains of trans persons are more in keeping with their gender than their sex. It has been found, for instance, that male-to-females show sex-atypical hypothalamus activation when smelling odorous steroids. Their sense of smell is more in keeping with their gender expression than their birth sex assigned (Berglund, Lindstrom, Dhejne-Helmy, & Savic, 2008). Tests of hearing also reveal significant differences. Tests of dichotic listening, the ability to distinguish similar but different sounds, e.g. tic and toc, when simultaneously presented to each ear, have also revealed actual brain “hard-wired” differences among trans women when compared with typical males. In regard to hearing their dichotic performance is more in keeping with their female gender than with their male sex (Govier, Diamond, Wolowiec, & Slade, 2010). And Burke et al. have reported finding differences in response to click-evoked otoacoustic emissions (CEOAEs). These are sounds experienced within the inner ear after an initial stimulus click is presented. Trans girls, those males with gender dysphoria, were found to have more female-typical responses than boy-typical responses. And these differences were even found in neonates (Burke, Menks, Cohen-Ketteinis, Klink, & Bakker, 2014).
Before leaving this topic of brain differences it is pertinent to remark that a difference between the brain functioning of adults and that of young children has been noted. Reiner, for example, who has a great deal of experience with both transsexual and intersex children has commented that “my own clinical experience would have to be interpreted as implying strongly that the brain states of the children (or of the adolescents, when they become adolescents) is quite different than the brain states of the adults.” (Reiner, personal communication, 2016).
Significant dental differences have even been found that differentiate trans persons. Antoszewski et al. found the metric features of teeth from trans men have an intermediate pattern between cisgender men and women (Antoszewski, Zadzińska, & Foczpański, 2009).
While more conclusive experimental data in support of the thesis presented is desirable, two recent publications have appeared that amplify and review much of the material discussed above, a paper entitled “Evidence Supporting the Biologic Nature of Gender Identity” and Bevan’s book with the title “The Psychobiology of Transsexualism and Transgenderism” (Bevan, 2015; Saraswat, Weinand, & Safer, 2015). To this investigator there seems evidence enough to consider trans persons as individuals intersexed in their brains and scant evidence to think their gender transition is a simple and unwarranted social choice.
Components and aspects of the material presented here, within a much broader context, have previously been introduced (Kraus, 2011).
My many thanks and much appreciation is due to those colleagues who have assisted me in the writing and review of this chapter. I take responsibility for any faults within, however. All faults are my own.