Literature Review Sexual Differentiation of the Human Brain: a nature/ Nurture Debate for the Etiology of Transsexualism

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Human Reproductive Biology 316

Literature Review

Human Reproductive Biology 910.316

Literature Review

Sexual Differentiation of the Human Brain:

A Nature/ Nurture Debate for the Etiology of Transsexualism
17th October 2005
Caroline Motteram


1. Introduction 2
2. The Nature /Nurture Debate: Theories of Psychosexual Development 2
2.1 The Nurture Debate 2

2.1.1 Psychosexually-neutral-at-birth theory 2-3

2.1.2 Psychoanalytic Theories 3-4
2.2 Nature debate 4

2.2.1 Genetic Effects 5 Sex determining genes 5 Genetic abnormalities 5-6
2.2.2. Epigenetic effects 7 Stressful situations 7 Endocrine Disrupters 7-8

      1. Recent Studies into the sexually dimorphic structures of the brain and transsexualism 8 Dr Swaab and The BSTc and Transsexualism 8-9 Dr Vilain:discovery of sexually differentiating genes prior to SRY gene activation 9

3. Nature or Nurture and the Public health Implications 10-11
4. Appendices 12
5. References 13-14

1. Introduction

Transsexualism is a controversial issue that has received much attention in both the media and academic fields. Recent occurrences such as the case of Kevin and Jennifer in the Family court of Australia (2001-2003), the suicide of female-to-male (FTM) transsexual David Rimmer last year, and the Four Corners coverage of “the Gender Puzzle” (2005) have again brought about public awareness of this topical issue.

The concept of gender identity remains largely controversial due to the many possible manifestations of gender. Genital appearance at birth, gonads and chromosomes are not completely reliable determinants of an individual's sex. While in the majority of the population these markers are congruent with innate sexual identification, in transsexualism, as with a number of other conditions such as CAH and AIS, these commonly used predictors of an individual's sex are ineffective (Johnson 2004). For the 1 in 30 000 male-to-female (MTF) and the 1 in 100 000 female-to-male (FTM) transsexuals, incongruity exists between the sexually differentiated features of the individual’s body and the individual’s brain and legal sex. These individuals may experience episodes of depression and anxiety, along with extreme personal discomfort (dysphoria). Due to the uncertainty surrounding the etiology of the condition much debate remains about treatment of gender dysphoria.

Current literature indicates that there is a nature/ nurture debate over the origins of the condition. Some argue that gender identity has biological underpinnings, while others claim that gender is a manifestation of social and rearing conditions. Both have implications for the assignment of gender at birth. Incorrect assignment can have lifelong negative repercussions for the individual and thus it is critical that physicians are fully informed as to the determinants of gender. The following report explores the nature/ nurture debate over the etiology of gender identity, specifically focusing on transsexualism. Further, it discuses the implications for public health regarding the treatment of such conditions.

2. The Nature /Nurture Debate: Theories of Psychosexual Development
2.1 The Nurture Debate

2.1.1 Psychosexually-neutral-at-birth theory

According to Money, Hampson & Hampson (1955, cited in Diamond 1965) children are born without any innate gender identity, and that they may only acquire one through the learning or imprinting processes that occurs during early socialization. The authors suggest that the critical period of gender identity development (imprinting of appropriate gender and social role) exists between the first 2½ -3 years of life. Thereafter, these individuals are supposedly unable to negotiate a change in their gender role without severe emotional trauma (Hampson and Hampson, 1961). Under this framework it is assumed that gender identity is independent of chromosomal sex, gonadal sex, genital morphology, hormonal balance, or other commonly used indicators of sex.

The authors provide a variety of case samples to validate their theory. Gonadal (presence of ovary or testis) and phenotypic sex (male or female external genitalia) is typically used to differentiate gender. In their studies the authors found that “where the sex of rearing was contradictory to the sex of the external genitalia, 23 of 25 individuals involved had been able to come to terms with their anomalous appearance and to establish a gender role consistent with their assigned sex and rearing” (Hampson and Hampson, 1961). Money also referred to the specific ‘Joan/John’ case to provide further evidence in support of his theory. In this case the male infant underwent an unsuccessful circumcision wherein the penis was burnt off. Following this the infant underwent sexual reassignment surgery (SRS) to become a female. Money indicated that the individual was successfully socialised and reared as a female without experiencing episodes of gender dysphoria. At the time this was a revolutionary case that validated Money’s assertion of sexual neutrality at birth.
2.1.2 Psychoanalytic Theories

Psychoanalytic theories on the development of gender identity disorders typically involve dysfunctional parent-child relationships. Ethel Person and Lionel Ovesey (1978, cited in Green & Blanchard 2000) claim that transexualism in males originates from unresolved separation anxiety during the separation-individuation phase of infantile development. The authors suggest that in order to cope with this anxiety, the child resorts to a reparative fantasy of symbiotic fusion with his mother. Adult transsexualism may be understood as an attempt to master that anxiety through sex reassignment surgery, through which the transsexual acts out his unconscious fantasy and symbolically becomes his mother (Green & Blanchard, 2000).

Just as obscure is a theory put forward by Robert Stoller (1974) to explain the etiology of transsexualism in a specific group of biological males, who would fall within the DSM-IV category of gender identity disorder. The theory beings with the grandmother of the future transsexual who treats her daughter coldly and neither encourages nor models femininity in her. The daughter establishes a close relationship with her father who encourages masculinity in her. Consequently, on an unconscious level the female develops and retains a strong penis envy. When the mother gives birth to an infant son, the male, who represents her feminized phallus, fulfills her lifelong wish for a penis (Stoller 1974, cited in Green & Blanchard, 2000). The mother-son interaction includes excessively close and prolonged body contact as the mother's behavior expresses her need to treat her son an extension of her own body. The transsexual's early experiences, especially the continuous skin-to-skin contact, produce an over identification with his mother, a blurring of ego boundaries, and eventually a feminine gender identity (Stoller 1974, cited in Green & Blanchard, 2000).
2.2 Nature debate

By the mid 1960's, animal studies were indicating that hormones have a much more powerful effect on sexual development and adult behaviour than the psychosexually-neutral-at-birth adherents had admitted (Diamond, 1965). It was discovered that during the critical periods of development, androgens and their metabolites organise the brain to produce life long, irreversible effects on a variety of reproductive and non-reproductive sexually dimorphic behaviours (‘organisational’ influences). Further, research indicated that sex steroids exert ‘activational’ influences throughout development most noticeably during the neonate period, puberty and adulthood due to the surge of gonadotrophins at each critical period. The Female hormone oestrogen was found to have a feminising effect on behaviour, while the male androgen testosterone was found to have a masculinising effect.

Dr Diamond challenged Dr Money’s assertion that sexual identity is a social construct that can be shaped by life experiences/rearing and altering an infants genitals. Using the renowned John/Joan case study, Diamond found that Money had misinterpreted and misrepresented the data to support his theory (Kotula 2002). While Money claimed that the child had successfully adapted to the change, in reality, the individual identified as being male despite the absence of a penis, having a feminine body with breasts and being reared as a female. Thus, what was once a landmark case to prove the influence of nurturing is now regarded as “significant to the theory of a biological premise in the formation of sexual identity” (Kotula 2002). To this end, Dr Diamond (cited in Wallbank 2003) cited ‘brain sex’ as a biological reality that explains aspects of sexual identity.

The nature debate holds that psychosexual differentiation and the determinants of gender identity have biological and neurobiological underpinnings. That is, it is assumed that gender (male or female orientation) is an innate ‘hard-wired’ construct that that may be induced by a number of factors, including manipulation of the hormonal environment during development (Asscheman 2004, cited in Johnson 2004). Manipulation of the hormonal environment derives from either genetic effects (sex determining genes or genetic abnormalities) or epigenetic effects (stressful situations or endocrine disruptors). The following will explore these determinants.

2.2.1 Genetic Effects Sex determining genes

Until the 1990’s gender was thought to be largely about chromosomes. However, this principle was challenged by a team of professors, including Professor Andrew Sinclair who discovered the SRY gene on the male Y chromosome. This gene is activated at around the seventh week of development and produces an enzyme called testes determining factor (TDF) which is primarily responsible for differentiation of the fetus down the male developmental line. The differentiated testes produce testosterone/ dihydrotestosterone and anti-mulleriam hormone (AMH) which have a masculinising (internal and external genitalia) and defeminizing (mullerian duct regression) effect respectively. In the absence of the SRY gene, the fetus differentiates down the female developmental line. The Wolffian duct system regresses and the female internal and external genitalia differentiate.

The sex hormones also lead to sexual differentiation of the CNS. In fact, animal studies indicate that manipulation of the hormonal environment during perinatal development permanently alters both the structure and function of the CNS (Gorski 1998). That is, by exposing females to testicular hormones masculinizes components of the CNS, while prenatal chemical castration or surgical castration of the male allows the development of a more female-like CNS (Gorski 1998). This has biological implications for the sexual differentiation of the brain down masculine or feminine lines. Genetic abnormalities

Animal studies looking at the structural sex differences between the male and female brain both prenatal and postnatal, indicate that sex differences are the result of exposing the developing CNS to circulating androgens (Gorski 1998). Specifically, rat studies focusing on the sexually dimorphic nucleus of the pre-optic area (SDN-POA), a structure known to be involved in the regulation of reproductive behaviour, have been important in demonstrating this connection. In humans this connection is more difficult to establish due to the ethical issues involved with manipulating the pre and/or postnatal hormonal environment. However, individuals with genetic abnormalities such as Androgen insensitivity syndrome (AIS) and congenital adrenal hyperplasia (CAH) are useful in demonstrating the organisational and activational influence of hormones on sexual differentiation of the brain and an individuals subsequent gender self-identity.

AIS is a condition in which a genetic male with normal testes (gonadal sex) cannot respond to testosterone due to the complete or partial absence of androgen receptors. While such an individuals genetic (presence of SRY gene), chromosomal (presence of Y chromosome), and gonadal sex (presence of testis) indicates that they are male, their phenotypic sex (female external genitalia) and behavioural sex (female gender-self identity) indicates otherwise. This presents a case for the role of gonadal hormones in the sexual differentiation of the human brain function. Importantly, it is useful in understanding the biological basis for the conflict between ones ‘core’ sex and their contradictory gonadal and phenotypic sex.
Similarly, females born with CAH (1 in 5000 females), a condition in which there is an excess of adrenal androgens in fetal life due to an enzyme deficiency (cortisol precursor 21-deoxycortisol), are likely to experience gender dysphoria (The Nature and Nurture of Gender 2005). Figure 1 (The Nature and Nurture of Gender 2005) demonstrates how the enzyme deficiency disturbs the normal HPA/HPG control mechanism and leads to masculinised external genitalia. Females with this condition are born with ambiguous external genitalia (see figure 2, The Nature and Nurture of Gender 2005) which necessitates SRS and cortisol supplementation postnatally. Despite these therapeutic interventions, female with this condition show increased male-like patterns of behaviour and are more likely to identify with being ‘male’ despite embodying female genetic and chromosomal sex. This demonstrates the powerful organising effect of hormones prenatally.

Studies reveal that adrenal androgen excess during the critical period of brain organisation is associated with a “genetic predisposition to androgen-dependent development of transsexualism in females” (Dorner, Poppe, Stahl, Kolzsch & Uebelhack 1991). Further, significantly increased basal plasma levels of dehydroepiandrosterone sulfate (DHEA-S) were found in male-to-female transsexuals as compared to normal males, suggesting partial 3 beta-ol hydroxysteroid dehydrogenase deficiency to be a predisposing factor for the development of male-to-female transsexualism (Dorner, Poppe, Stahl, Kolzsch & Uebelhack 1991).

Figure 1. HPA/HPG activity of a normal Figure 2. Female with CAH resulting

Individual and an individual with CAH in ambiguous genitalia at birth

2.2.2. Epigenetic effects

Epigenetic effects demonstrate how endogenous hormones (hormones produced in the body) that guide sexual development and function can be mimicked, blocked, modulated, or otherwise upset by stressful situations or by many man-made and/or natural chemicals widely used in virtually every aspect of modern life (National Research Council, cited in Johnson 2004). Stressful situations

Dr Glenn Wilson, from London's Institute of Psychiatry (cited in Coleman 2003), believes that hormones play a big part in gender identity. "If there is maternal stress during pregnancy, this can block the effect of emasculating or feminising hormones at the point when the foetal brain development is establishing gender identity". This is due to the possible suppression of fetal testosterone activity in response chronically high levels of maternal steroid hormone cortisol. Maternal cortisol readily crosses the placenta and travels to the fetal brain, where it suppresses the release of the pituitary hormones FSH and LH, resulting in turn in a reduction of testosterone production. As previously mentioned testosterone suppression has a powerful feminising effect and allows for the development of a more female like CNS.

The first demonstration of a linkage between maternal stress and incomplete fetal masculinization came from a study examining males born in NAZI Germany during the latter stages of World War II. Because of the crumbling of the Third Reich and the intense bombing operations, mothers were under extreme stress throughout their pregnancies. The records reveal an extraordinarily high incidence of male homosexuality in this population, compared with control populations, thus supporting the maternal stress hypothesis (Fox, 2003). This also has implications for the incidence of transsexualism. It could be assumed that due to the suppression of testosterone in this critical stage of development, there would be a greater incidence of male-to-female transsexuals in children of mothers who experienced chronic stressful conditions during pregnancy. Endocrine Disrupters

Endocirne disrupters are environmental chemicals that disrupt the action of endogenous hormones. Those agents that mimic, block or modulate the activity of genes or sex hormones have the potential to disrupt the developing fetuses normal differentiation down male or female lines. For example, the pesticide DDT and its metabolites, display estrogenic, antiandrogenic, and inhibitory effects on the enzyme 3beta-hydroxysteroid dehydrogenase leading to increased levels of dehydroepiandrosterone and its sulfate (DHEA & DHEA-S) as precursors of endogenous androgens and estrogens. Studies examining the effects of the pesticide DDT on gender identify compared subjects born before DDT use to those born during its use. It was found that the prevalence of individuals with transsexualism was increased significantly in the order of 3-4 fold (Dörner, Poppe, Stahl, Kolzsch, & Uebelhack 1991).

      1. Recent Studies into the sexually dimorphic structures of the brain and transsexualism Dr Swaab and The BSTc and Transsexualism

In his revolutionary research into morphological differences in the male and female brain, Dr Swaab discovered a region of the brain called the “central subdivision of the bed nucleus of the stria terminalis” (BSTc) which seems to be linked to gender identity and sexual behavior. He studied the brains of 6 individuals postmortem and found that on average the section is 44% larger in heterosexual men than in heterosexual women (Swaab 1996, cited in Glausiusz 1996). Interestingly, his findings revealed that the BSTc for MTF transsexuals has female size, while the BSTc for FTM transsexuals has male size. The study suggested that gender identity develops as a result of an interaction between the developing brain and sex hormones. However, due to design the small sample size, the effect of hormonal exposure during adulthood could not be ruled out as a causal factor.

Extending from this study Kruijever and associates studied the brains of 42 individuals; eight of these were gender dysphoric individuals, six whom were MTF transsexuals (who had undergone SRS and HRT), one MTF transsexual (who had no treatment whatsoever) and one FTM individual. Among the control group there were; nine homosexual men, nine heterosexual men, ten presumed heterosexual women, three women with hormone disorders and three men with hormone disorders. The study sort to measure the number of SOM neurons in the BSTc in relation to sex, sexual orientation, gender identity and past or present hormonal status.
Controlling for sexual orientation and hormonal exposure during adulthood, the results supported the previous findings that there is 1. a sex difference in the SOM neurons in the human BSTc with males having almost twice as many as females; 2. the number of SOM neurons in the BSTc of the MTF transsexuals is in the female range; and 3. the opposite pattern in the BSTc of a FTM transsexual with a SOM neurone number in the male range (Kruijver, Zhou, Pool, Hofman, Gooren, & Swaab2000). Figures 3 and 4 demonstrate these findings. For further justification of findings see summary of results in Appendix 1.

Figure 1. BSTc neuron numbers. Distribution of the BSTc neuron numbers among the different groups according to sex, sexual orientation, and gender identity. M, Heterosexual male reference group; HM, homosexual male group; F, female group; TM, male-to-female transsexuals.

Figure 2. Representative immunocytochemical stainings of the somatostatin neurons and fibers in the BSTc of a reference man (a), reference woman (b), homosexual man (c), and male-to-female transsexual (d). Note the sex difference regardless of sexual orientation. The male-to-female transsexual has a BSTc in the female range. Dr Vilain and discovery of sexually differentiating genes prior to SRY gene activation

Recent research by Dr Vilain and his associates suggests that hormones are only partially responsible for brain sexual differentiation. While it was previously believed that hormones were primarily responsible for male and female brain differentiation, it is now hypothesised that genes are linked to gender and exert effects prior to SRY gene activation.

From Dr Vilain’s research, it appears that in mice 54 candidate or possible genes are responsible for brain sexual development inducing neural differences of male and female before the gonads develop or produce sex hormones (Dewing and Vilain, cited in Richards 2004). The geneticist found that of the 54 genes, 18 were produced at higher levels in the male, and 36 were produced at higher levels in the female. Further, it was found that these genes in the embryo are turned on differently in the male and female brains, even before the gonadal differentiation occurs.
This exciting new finding presents a whole new spectrum of possible biological determinants of gender. According to Harley (cited in 2005) this may help scientists to explain why some people identify as one gender or the other, independently of their chromosomes.
3. Nature or Nurture and the Public health Implications

According to Diamond (1965) arguments over the possible causes of transsexualism have essentially revolved around disagreements over the relative importance of genetics, hormones, and socialization on the development of gender identity, resulting in a kind of nature/nurture debate that has affected both theories as well as clinical approaches to treatment. While this report discussed the possible etiology of transexualism form a nature and nurture perspective, it is obvious form the text dedicated to the genetic and epigenetic (hormonal) determinates of gender identity that gender identity is considered to have strong biological underpinnings. Despite this, it would be naïve to suggest that phonotypical behavioral polymorphisms are solely determined by genes/hormones. Thus, we cannot dismiss environmental socialization and rearing conditions as potential determinants of gender. In reality, the interaction of genes, hormones and environmental factors are likely to be associated with gender dysphoric conditions.

Because there is currently no known method of determining at birth if a person will identify psychologically as male or female in adulthood, it is possible for the wrong decision to be made regarding sex of rearing (Reiner, 2004), often leading to surgical reassignment of the neonate to the female anatomical sex because it is technically simpler to surgically construct a vagina than a penis. (Diamond & Sigmundson, 1997, cited in Johnson 2004). As mentioned, inappropriate reassignment can have devastating repercussions for those involved. The recent research looking at the sexually dimorphic structures in the brain between the ‘normal’ and transsexual population may prove useful in uncovering an individuals ‘core’ sex so as to correctly assign an individual with ambiguous genitalia to the correct sex. While current imaging techniques such as MRI and PET scans are unable to detect the variations in the brains of transsexuals (Gorman 1995), perhaps in the future there may be technology that permits such detection.
Dr Vilain’s finding, while still in the early phases of research, presents an exciting new possibility for the detection of innate sex. He suggests that if genetic variants associated with the gender that a person feels they belong to can be identified, then it may one day be possible to take a blood sample from a young intersex patient to determine which of these DNA sequences they carry. "If there was a biological tool that could predict the likely gender of a person based on their DNA sequence, that would be very useful for intersex children" (Vilain, cited in Dennis 2004).

Establishing a biological basis to gender dysphoria may be important in eradicating the social stigma attached to transsexuals. Viewing the disorder as a manifestation of a congenital biological condition rather than an alternative lifestyle choice will require educating health care providers, practicing physicians and the general public. Once a biological basis is established, public policy reform should ensue. The condition should be treated as a birth defect among government and medical leaders. Thus, allowances should be made for insurance coverage for HRT, electrolysis, SRS and any other treatment that the condition necessitates.

4. Appendices
Appendix 1. Summary of findings of study “Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic Nucleus” (Kruijver 2000)
The sex hormone disorder patients S1, S2, S3, S5, S6, and M2 indicate that changes in sex hormone levels in adulthood do not change the neuron numbers of the BSTc. The difference between the M and the TM group (P < 0.04) is also statistically significant according to the sequential Bonferonni method if S2, S3, and S5 are included in the M group or if S7 is included in the TM group (P 0.01). Note that the number of neurons of the FMT is fully within the male range. Whether the transsexuals were male oriented (T1, T6), female oriented (T2, T3, T5), or both (T4) did not have any relationship with the neuron number of the BSTc. The same holds true for heterosexual and homosexual men. This shows that the BSTc number of somatostatin neurons is not related to sexual orientation. A, AIDS patient. The BSTc number of neurons in the heterosexual man and woman with AIDS remained well within the corresponding reference group. So AIDS did not seem to affect the somatostatin neuron numbers in the BSTc. P, Postmenopausal woman.

  • S1 ( 46 yr of age): adrenal cortex tumor for more than 1 yr, causing high cortisol, androstendione, and testosterone levels.

  • S2 ( 31 yr of age): feminizing adrenal tumor that induced high blood levels of oestrogens.

  • S5 ( 86 yr of age): prostate carcinoma; prostatectomy; orchiectomy, and antiandrogen treatment for the last 2 yr.

  • S6 ( 25 yr of age): Turner syndrome (45,X0; ovarian hypoplasia).

  • M2 ( 73 yr of age): postmenopausal status.

5. References

Coleman, N. (2003), August 20-last update, ‘Boys will be girls’, The Guardian, [Online], Available:,3605,1021949,00.html.

Diamond, M. (1965), ‘A Critical Evaluation pf the Ontology of Human Sexual Behaviour’, The Quarterly Review of Biology, [Online], vol.40, no.2, pp 148-175. Available: JSTOR.

Dennis, C. (2004), “The most important sexual organ”, Nature, [Online], Vol.427, Iss. 6973; pg. 390. Available: Proquest.

Dorner, G., Poppe, I., Stahl, F., Kolzsch, J. & Uebelhack R. 1991, ‘Gene- and environment-dependent neuroendocrine etiogenesis of homosexuality and transsexualism’ Clinical Endocrinology, [Online], vol.98, no.2, pp141-150. Available: PubMed.

Fox, S. (2003), ‘Biological Underpinnings of Gender Identity Conditions’, Sarah’s Place. Available:
Glausiusz, J. (1996), ‘Transsexual brains’, Discover, [Online], vol.17, iss. 1; pg. 83. Available: Proquest

Gorman, C. (1995), ‘Trapped in the body of a man?’, Time, [Online], vol.146, iss. 20; pg. 94-96. Available: Proquest.

Gorski, R.A. (1998), Development of the Cerebral Cortex: Sexual Differentiation of the Central Nervous System, American Academic Child Adolescence Psychiatry , [Online], , vol.37, issue 12. pp.1337-1339. Available: FTMA Network.

Hampson, J. L., & Hampson, J. G. (1961), The ontogenesis of sexual behavior in man, p. 1401-1432. In W. C. Young (ed.), Sex and Internal Secretions, 3rd ed., Williams and Wilkins, Baltimore.
Johnson, C. (2004), ‘Transsexualism: An Unacknowledged Endpoint of Developmental Endocrine Disruption’, The Evergreen State College pp.1-212.

Kotula, D. (21 July 2005), A Conversation with Dr Milton Diamond from "In the Realm of the Phallus Palace" [Online], FTM Australia. Available:

Kruijver, F., Zhou, J-N., Pool, C., Hofman, M., Gooren. L. & Swaab, D. (2000), “Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic Nucleus”, Journal of Clinical Endocrinology & Metabolism [Online], Vol 85. No: 5, 2034-2041. Available:

McEwen, B.S, 1999, ‘Permanence of brain sex differences and structural plasticity of the adult brain’, The National Academy of Sciences, [Online], vol.96, no.13, pp.7128-7130. Available: PubMed.
Richards, D. (2004), Brain Gender Identity, [Online], Transgender Medical. Available:
‘Sexual Identity Hard-Wired by Genetics’ 2003, Molecular Brain Research, [Online], Oct. 21 issue, Vol. 118, pgs. 82-90. Available:
The Nature and Nurture of Gender (2005), The University of Plymouth, Available:
Wallbank, K. (2003), ‘The Legal Environment Following Re Kevin: New Perceptions And Strategies For Effective Law Reform’, Men’s Australian Network [Online]. Available:


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