Australian researchers have identified a significant link between a gene involved in testosterone action and male-to-female transsexualism.
DNA analysis from 112 male-to-female transsexual volunteers showed they were more likely to have a longer version of the androgen receptor gene. The genetic difference may cause weaker testosterone signals, the team reported in Biological Psychiatry. However, other genes are also likely to play a part, they stressed. Increasingly, biological factors are being implicated in gender identity. The study has shown that certain brain structures in male-to-female transsexual people are more “female-like”. In the latest study, researchers looked for potential differences in three genes known to be involved in sex development – coding for the androgen receptor, the Estrogen receptor and an enzyme which converts testosterone to Estrogen.
Comparison of the DNA from the male to female transsexual participants with 258 controls showed a significant link with a long version of the androgen receptor gene and transsexualism.
It is known that the longer version of the androgen receptor gene is associated with less efficient testosterone signalling. This reduced action of the male sex hormone may have an effect on gender development in the womb, the researchers speculated. “We think that these genetic differences might reduce testosterone action and under masculinize the brain during Foetal development,” said researcher Lauren Hare from Prince Henry’s Institute of Medical Research. Co-author Professor Vincent Harley added: “There is a social stigma that transsexualism is simply a lifestyle choice, however, our findings support a biological basis of how gender identity develops.”
Although this is the largest genetic study of transsexualism to date, the researchers now plan to see if the results can be replicated in a larger population. Terry Reed from the Gender Identity Research and Education Society said she was convinced of a biological basis to transsexualism. “This study appears to reinforce earlier studies which have indicated that, in some trans people, there may be a genetic trigger for the development of a typical gender dysphoria – identity issue. “However, it may be just one of several routes and, although it seems extremely likely that a biological element will always be present in the aetiology of transsexualism, it’s unlikely that developmental pathways will be the same in all individuals.”
Gender Identity Disorder is defined as an incongruence between the physical phenotype and the gender identity1], that is, the self-identification as male or female. The experience of this incongruence is termed Gender Dysphoria. The most extreme form, in which individuals need to adapt their phenotype with hormones and surgery to make it congruent with their gender identity, is called transsexualism2], Those individuals experiencing this condition are referred to as people, that is, trans men (female to male) and trans women (male to a female).
Transsexualism can be considered to be a -developmental condition of the brain. Several sexually dimorphic nuclei have been found in the area of the brain (Allen & Gorski, 1990; Swaab et. ., 2001). Of particular interest is the sexually dimorphic limbic nucleus called the central subdivision of the bed nucleus of the stria terminalis (BSTc) which appears to become fully sexually differentiated in the human brain by early adulthood. This nucleus has also been found to be sexually dimorphic in other mammalian and avian species (Miller et. ., 1989; Grossmann et. ., 2002). In human males, the volume of this nucleus is almost twice as large as in females and its number of neurons almost double (P <0.006) (Zhou et. ., 1995; Kruijver et. ., 2000; Chung et. ., 2002).
3. The Kruijver et. al. study, cited above, indicates that in the case of transsexualism this nucleus has a sex-reversed structure. This means that in the case of trans women (n=7), the size of this nucleus and its neuron count was found to be in the same range as that of the female controls (n=13) and, therefore, women in the general population. In the only available brain of a trans man, the volume and structure of this nucleus was found to be in the range of the male controls (n=21) and, therefore, men in the general population. It is hypothesized that this male-like BSTc will be present in other trans men as well. These findings were independent of sexual orientation and the use of exogenous sex hormones. In the 42 human brains collected for this study, the BSTc was found to have a structure concordant with the psychological identification as male or female. It is inferred that the BSTc is an important part of a sexually dimorphic neural circuit and that it is involved in the development of gender identity (Kruijver et. al., 2000).
4. Sexual differentiation of the mammalian brain starts during foetal development and continues after birth (Kawata, 1995; Swaab et. al. 2001). It is hypothesized that in humans, in common with all other mammals studied, hormones significantly influence this dimorphic development, although, at present, the exact mechanism is incompletely understood. It is also postulated that these hormonal effects occur at several critical periods of development of the sexual differentiation of the brain during which gender identity is established, initially during the foetal period, then around the time of birth; and also post-natal. Factors which may contribute to an altered hormone environment in the brain at the critical moments in its early development might include genetic influences (Landèn, 1999; Coolidge et. , 2002) and/or medication, environmental influences (Diamond et al, 1996; Whitten et. al, 2002), stress or trauma to the mother during pregnancy (Ward et. al, 2002; Swaab et. al, 2002).
5. Gender identity usually continues along lines which are consistent with the individual’s phenotype, however, a very small number of children experience their gender identity as being incongruent with their phenotype. Adult outcomes in such cases are varied and cannot be predicted with certainty. It is only in a minority of these children that, regardless of phenotypical socialization and nurture, this incongruence will persist into adulthood and manifest as transsexualism (Green, 1987; Ekins, 1997; Prosser, 1998; Di Ceglie, 2000; Ekins & King, 2001; Bates, 2002).
6. As stated, in trans people, a sex-reversed BSTc has been found. The findings of a specific sex-reversed brain organization in trans people provide evidence consistent with the concept of a biological element in the aetiology of transsexualism. The evidence for an innate biological predisposition is supported by other studies, one example of which indicates a higher than average correlation with left-handedness (Green & Young, 2001). Where the predisposition for transsexualism exists, psycho-social and other factors may subsequently play a role in the outcome, however, no evidence that nurturing and socialization in contradiction to the phenotype can cause transsexualism, nor that nurture which is entirely consistent with the phenotype can prevent it (Diamond, 1996). There is further clear evidence from the histories of conditions involving anomalies of genitalia, that gender identity may resolve independently of genital appearance, even when that appearance and the assigned identity are enhanced by medical and social interventions (Imperato-McGinley, 1979; Rösler & Kohn, 1983; Diamond, 1997; Diamond & Sigmundson, 1997; Kipnis & Diamond, 1998; Reiner, 1999; Reiner, 2000). It is not possible to identify one single cause for transsexualism: rather, its causality is highly complex and multifactorial. The condition requires a careful diagnostic process, based largely on self-assessment, facilitated by a specialist professional.
7. In conclusion, transsexualism is strongly associated with the neurodevelopment of the brain. (Zhou et.al. 1995; Kruijver et. al. 2000). The condition is not overcome by contrary socialization, nor by psychological or psychiatric treatments alone (Green, 1999). Individuals may benefit from an approach that includes a program of hormones and corrective surgery to achieve realignment of the phenotype with the gender identity, accompanied by well-integrated psychosocial interventions to support the individual and to assist in the adaptation to the appropriate social role (Green and Fleming, 2000). Treatments may vary and should be commensurate with each individual’s particular needs and circumstances.
 The term ‘gender identity’ is used, in the UK, to indicate the self-identification as male or female. However, terminology varies around the world, and the term ‘sexual identity’ is preferred by many in the US.(pace Professor Milton Diamond). See “Sex and Gender are different: Sexual Identity & Gender Identity are Different”, (2000) Clinical Psychology & Psychiatry, Vol 7 (3): 320-334.
 The transsexual condition is also referred to in various ways (Diamond M, 2002 In Press) “What’s In a Name? Some terms used in the discussion of Sex and Gender”. Transgender Tapestry.