Brain Sex Theory (Neuro-biological sex differentiation)

In 2002, Professor Diamond asked:

“…since there is little evidence that they [men and women with transsexualism] have been brought up in anything but typical circumstances, and there is no obvious ambiguity in their biology, the question arises – How do the feelings of being of the opposite sex develop? The simple answer is – In the brain.”

Dr William Reiner, a leading specialist in the treatment of children with ambiguous genitalia, agrees:

“…the organ that appears to be critical to psychosexual development and adaptation is not the external genitalia, but the brain.”(1)

The brain-sex (neurobiological) theory(2) is based on research which suggests there are a number of sections in the human brain which appear to be different between males and females.(3) These areas called sexually dimorphic structures.

The sexually differentiated areas of the brain can contribute to many different biological variations(4) that occur in human sexual formation, of which transsexualism (TS) is only one. Studies in 1990(5) and 1995(6) offer evidence that the brains of transsexual people are similar to the brains typical of their target sex. These results were replicated in 2000(7) and 2001(8) and included controls to eliminate many of the weaknesses identified in the original research. All the studies highlighted the likelihood that TS is associated with brain structure(9) as a normal variation in human development.(10)

Research into TS continues to seek evidence for:

“…the formation of some kind of gender system within the brain that is fundamental to ultimate gender identity and gender-role development.”(11)

The brain-sex (neurobiological) theory entertains a large range of options rather than narrow alternatives due to illness, sin or malformation.(12) This generous theory posits TS as a variation of sex development and offers the most to practitioners as well as the men and women with the condition, to understand the possible cause to the predicament.

A practical explanation?

It has been assumed that sexual differentiation (development into a male or a female phenotype) is completed at birth.

However, research shows the physical sex of the child (genitals) and the sexual differentiation of the brain (neurobiological) are still in development at the point of birth and continue on until four years after birth.(13) This development has been identified to occur within four main processes of sexual differentiation in human development.


The first three steps occur between the time of conception up until birth (indicated by the middle line in the above diagram) and the last process after birth until around four years of age.(14)

  1. First, the karyotype (or the appearance of the chromosomal configuration) is established (usually XX or XY);
  2. next, gonadal differentiation (internal reproductive organs);
  3. next, differentiation of the internal and external genitalia (physical genital formation); and
  4. finally, the differentiation of the brain into male or female (brain-sex).(15)

Usually all the stages correlate or fit with each other, resulting in the formation of what we conventionally understand to be a sexed human being (male or female) with a matching congruent gender identity (girl or boy).

Before birth, the chromosomal configuration (such as XY for male or XX for female) usually gives rise to different gonadal development (ovarian or testicular), resulting in internal and external genitalia upon which legal-sex is eventually assigned. Physical phenotype is assigned by genetic and hormonal forces before birth and occurs sometime during the first three stages of development.

The final process of brain differentiation takes place after birth around the age of four years old. This is the starting point for specific sex-based behaviours and the development of the newborn’s gender identity. Gender identity develops as a result of an interaction between the developing brain and sex hormones.(16)

For most people, all four stages link together to create a harmonious physical sex development. For about one in 80 babies, there is some disharmony.(17) These infants are born with some kind of sex or gender identity anomaly.

The most common sex anomalies are due to chromosomal configurations in human beings such 47XXY, 47YYX, 47XXX, 47XYY, 45XO or mosaicism, which shows a variety of chromosomal configurations within the same individual. For these infants, the anomaly is easy to spot. A newborn with genitals not clearly male or clearly female is termed an intersex birth.

There are times when the anomaly is discovered much later in adulthood. Sometimes menstruation doesn’t occur as expected or after seeking medical help to conceive a child, medical tests show reproductive infertility or another anomaly. Given the effects of TS are not visible in external physical sex characteristics (like some other intersex births), individuals with TS are always assigned the sex opposite to their actual-sex at birth. The anomaly is only becomes evident when the child emphatically corrects a parent or other caregiver (I’m not a girl! I’m a boy!). Other children don’t necessarily voice their concerns, but they have a strong sense that something isn’t quite right.

In 2002, based on the accumulation of research after over 40 years of research, Professor Milton Diamond concluded:

“Transsexuals, who I believe are intersexed, have the body and genitals of one sex and the brain of the other.(18) In this respect, men and women affected by transsexualism are properly considered to have a variation of sex development or an intersex condition.”(19)

For a thorough discussion see Gurney (2004) Transsexualism as an intersex condition.


  1. Reiner, 1997.
  2. Hoenig, 1985; Reiner, 1997; Gooren, 2000; Besser et al., 2004.
  3. Nuclei in the hypothalamic area of the brain (Swaab & Fliers, 1985; Allen & Gorski, 1990;Swaab, et al., 2001; Chung, De Vries & Swaab, 2002); the central subdivision of the bed nucleus of the stria terminalis (BSTc), (Kruijver, et al., 2000; Gooren & Swaab, 2000; Chung, et al., 2002); the sexually dimorphic nucleus (SDN) of the preoptic nucleus of the hypothalamus is twice as large in males than females (Swaab & Fliers, 1985; Swaab & Hofman, 1988; Hofman & Swaab, 1989; Hofman & Swaab, 1991; de Courten-Myers, 1999; Kruijver, et al., 2000; Swaab, et al., 2001; Chung, et al., 2002); the suprachiasmatic nucleus (SCN) of the hypothalamus is elongated in females and more spherical, and twice as large in males (Swaab, Fliers & Partiman, 1985; Hofman & Swaab, 1991); adult females have been found to have more gray matter as compared with males, whereas adult males have been found to have more white matter compared with females (Gur et al., 1999; Swaab, et al., 2001; Chen, Sachdev, Wen & Anstey, 2007); the massa intermedia, a band of tissue which connects the two halves of the thymus is more likely to be absent in males than females (Allen & Gorski, 1990); posterior region of the corpus callosum was more bulbous in females than males (de Courten-Myers, 1999); females are more likely to be functionally symmetric with regard to cerebral hemispheres than males (Wisniewski, 1998); higher vasopressin plasma levels are reported for males compared to females (Swaab, et al., 2001).
  4. 5-alpha-reductase deficiency, Androgen insensitivity syndrome (AIS), Congenital adrenal hyperplasia (CAH), de la Chapelle syndrome (XX male), Klinefelter syndrome (XXY), Mosaicism XO/XY, Progestin-induced virilisation, Swyer syndrome (XY female), Triple X syndrome (XXX), Tetrasomy X syndrome(XXXX), Turner syndrome (XO), XYY syndrome (XYY) and there are many other conditions who do not follow the typical patterns.
  5. Allen and Gorski’s 1990 study was the first which directed attention towards the bed nucleus of the stria terminalis (BST). It claimed the nuclei of females were significantly smaller than those of the males.
  6. Zhou and colleagues 1995 study built on the Allen and Gorski 1990 study, which claimed the BST volumes for transsexual women (identified male at birth) were in the range of and even smaller those of the non-transsexual women and smaller than homosexual men. In nontranssexual males the volume of this nucleus is almost twice as large as in non-transsexual females and the number of neurons is almost double (Kruijver, et al., 2000). Zhou and colleagues study agreed the biological structure in the brains of transsexual women had a totally female pattern, not attributable to sex hormone therapy. The number of neurones in transsexual women was similar to that in non-transsexual women, whereas the number of neurones in transsexual men was similar to that in non-transsexual men. This appears to support a neurobiological basis to gender identity developing as a result of an interaction between the developing brain and sex hormones. At the time of the Zhou and colleagues’ 1995 study, it was presumed brain structures present at birth remained unchanged throughout adult life. Morris’ (2005) study showed volume differences in the brain altered and return to pre-treatment levels in male and female rats depending on the available androgens. In some brain structures, especially those rich in androgen and oestrogen receptors, there appears to be a considerable plasticity.
  7. Kruijver and colleagues’ 2000 study claimed, regardless of sexual orientation, non-transsexual males had almost twice as many somatostatin neurones as non-transsexual females and the volume of their BST nucleus is almost twice as large. Critics would argue it is unclear whether the small BST causes the condition or if it is simply a result of the complexity of the condition.
  8. Several sexually dimorphic nuclei have been found in the hypothalamic area of the brain (Swaab, et al., 2001).
  9. Chung, et al., 2002.
  10. Reid, 2004.
  11. Docter, (1988, p63).
  12. Hoenig, 1985; Reiner, 1997; Gooren, 2000; Besser et al. 2004.
  13. Gooren, 2000; Besser et al., 2004; Lavranos, Angelopoulou, Manolakou & Balla, 2006 refer to a “sexual brain model”.
  14. Swaab & Hofman, 1988; Clarke, Kraftsik, Van der Loos & Innocenti, 1989; Gooren, 1993; Kawata, 1995; Swaab, et al., 2001.
  15. Diamond: “Since the brain is the organ determining or scripting male or female behaviors, the term brain sex is short hand to reflect on how an individual thinks and organizes the world; whether in stereotypical male or female ways. It is certainly true that the brain is the most sexual organ of the body and the term brain sex reflects its male or female disposition. It directs the individual to think and act more like a stereotypic male or more like a female.” (2002, 36).
  16. Allen & Gorski, 1990; Zhou, et al., 1995; Kruijver, et al., 2000.
  17. Gooren, 1993.
  18. Diamond, 2000.
  19. As far back as 1957, it was suggested TS be considered an intersex condition:“…the definition of hermaphroditism should not be confined to those rare individuals with proved testes and ovaries but extended to include all those with indefinite sex attitudes.” (Giles and Millard); Gooren, 1993; Diamond, 2000, 2002; Playdon, (2000) advised the UK Government, TS be thought of as an intersex condition.; ReKevin, 2001.