Transsexual and Intersex Gender Identity

An evolving page, showing papers, URLs to those papers, and quotes (usually from the abstracts) showing the significance of those papers.

Peer-Reviewed Papers

First, a long meta-list of references. Some are repeated below, most are not. http://www.cakeworld.info/home/transsexualism/what-causes

Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling odorous steroids. by Berglund et al Cerebral Cortex 2008 18(8):1900-1908;
...the data implicate that transsexuality may be associated with sex-atypical physiological responses in specific hypothalamic circuits, possibly as a consequence of a variant neuronal differentiation.
Male–to–female transsexuals have female neuron numbers in a limbic nucleus. Kruiver et al J Clin Endocrinol Metab (2000) 85:2034–2041
The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.
Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation. Swaab Gynecol Endocrinol (2004) 19:301–312.
Solid evidence for the importance of postnatal social factors is lacking. In the human brain, structural diferences have been described that seem to be related to gender identity and sexual orientation.
A sex difference in the human brain and its relation to transsexuality. by Zhou et al Nature (1995) 378:68–70.
Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones
A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity. by Garcia-Falgueras et al Brain. 2008 Dec;131(Pt 12):3132-46.
We propose that the sex reversal of the INAH3 in transsexual people 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.

Discordant Sexual Identity in Some Genetic Males with Cloacal Exstrophy Assigned to Female Sex at Birth by Reiner and Gearhart, N Engl J Med. 2004 January 22; 350(4): 333–341.
RESULTS Eight of the 14 subjects assigned to female sex declared themselves male during the course of this study, whereas the 2 raised as males remained male. Subjects could be grouped according to their stated sexual identity. Five subjects were living as females; three were living with unclear sexual identity, although two of the three had declared themselves male; and eight were living as males, six of whom had reassigned themselves to male sex. All 16 subjects had moderate-to-marked interests and attitudes that were considered typical of males. Follow-up ranged from 34 to 98 months.
CONCLUSIONS Routine neonatal assignment of genetic males to female sex because of severe phallic inadequacy can result in unpredictable sexual identification. Clinical interventions in such children should be reexamined in the light of these findings.

The role of androgen receptors in the masculinization of brain and behavior: what we’ve learned from the testicular feminization mutation. Zulago et al. Horm Behav 53:613-626
The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity.

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. - Rametti et al, J Psychiatr Res. 2010 Jun 8.
CONCLUSIONS: Our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females). Our results provide evidence for an inherent difference in the brain structure of FtM transsexuals.

Regional cerebral blood flow changes in female to male gender identity disorder. - Tanaka et al, Psychiatry Clin Neurosci. 2010 Apr 1;64(2):157-61.
RESULTS: GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects.
CONCLUSIONS: The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.

“Prenatal hormones versus postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia” Pasterski VL, Geffner ME, Brain C, Hindmarsh P, Brook C, Hines M Child Dev 76(1):264-78 2005
Data show that increased male-typical toy play by girls with CAH cannot be explained by parental encouragement of male-typical toy play. Although parents encourage sex-appropriate behavior, their encouragement appears to be insufficient to override the interest of girls with CAH in cross-sexed toys.

Sexual Hormones and the Brain: An Essential Alliance for Sexual Identity and Sexual Orientation Garcia-Falgueras A, Swaab DF Endocr Dev. 2010;17:22-35
The fetal brain develops during the intrauterine period in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed or organized into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in extreme cases in trans-sexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no indication that social environment after birth has an effect on gender identity or sexual orientation.
and also
Boys and girls behave in different ways and one of the stereotypical behavioral differences between them, that has often been said to be forced upon them by upbringing and social environment, is their behavior in play. Boys prefer to play with cars and balls, whereas girls prefer dolls. This sex difference in toy preference is present very early in life (3–8 months of age) [1]. The idea that it is not society that forces these choices upon children but a sex difference in the early development of their brains and behavior is also supported by monkey behavioral studies. Alexander and Hines [2], who offered dolls, toy cars and balls to green Vervet monkeys found the female monkeys consistently chose the dolls and examined these ano-genitally, whereas the male monkeys were more interested in playing with the toy cars and with the ball....

AMH and AMH receptor defects in persistent Müllerian duct syndrome by Josso et al Human Reproduction Update, Volume 11, Number 4, July 2005 , pp. 351-356(6)
Mutations of the AMH and AMH receptor type II (AMHR-II) genes lead to persistence of the uterus and Fallopian tubes in males. Both conditions are transmitted according to a recessive autosomal pattern and are symptomatic only in males. Affected individuals are otherwise normally virilized, undergo normal male puberty; and may be fertile if testes, tightly attached to the Fallopian tubes, can be replaced in the scrotum

Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes. by Holterhus et al BMC Genomics. 2009 Jul 1;10:292.
CONCLUSION: A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.

Male Gender Identity in Complete Androgen Insensitivity Syndrome by T'sjoen et al. Arch Sex Behav. 2010 Apr 1.
The patient qualifies as female-to-male transsexual and was treated according to the Standards of Care by the World Professional Association for Transgender Health with good outcome. However, we do not believe that female sex of rearing as a standard procedure should be questioned in CAIS. Our case challenges the role of a functional AR pathway in the development of male gender identity.

Biological and Psychosocial Correlates of Adult Gender‐Variant Identities: a Review by J.F.Veale & D.E.Clarke, Personality and Individual Differences (2009) 48(4), 357-366 (PDF)
We conclude that biological factors, especially prenatal androgen levels, play a role in the development of a gender-variant identity and it is likely that psychosocial variables play a role in interaction with these factors.

True hermaphroditism with oogenesis and spermatogenesis. Shannon R, Nicolaides NJ. Aust NZ J Obstet Gynaecol. 1973 Aug;13(3):184-7
True hermaphroditism exists when both ovarian and testicular tissues are present in the same person. This condition is quite rare and it is particularly rare for the subject to exhibit oogenesis and effective spermatogenesis.
(A fertile individual who has fathered two children can have an ovary with follicles and devloping ova. This individual also has a Fallopian tube and a uterus. - M.Italiano)

Sexual differentiation of the human brain in relation to gender identity and sexual orientation D.Swaab & A.Garcia-Fulgaras Functional Neurology, Jan-Mar 2009:
One person we studied had untreated male gender dysphoria (S7), took no hormones and kept his transsexual feelings under wraps. He appeared to have a large INAH3 volume - in the male range - but a female INAH3 number of neurons (68) and a female BSTc somatostatin neuron number (95). Hence, this individual's hypothalamic characteristics were mid-way between male and female values


Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation
by Uhlenhaut et al, Cell, Volume 139, Issue 6, 1130-1142, 11 December 2009:
Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women

Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure by Pol et al, Europ Jnl Endocrinology, Vol 155, suppl_1, S107-S114 2006
Objective: Sex hormones are not only involved in the formation of reproductive organs, but also induce sexually-dimorphic brain development and organization. Cross-sex hormone administration to transsexuals provides a unique possibility to study the effects of sex steroids on brain morphology in young adulthood.

Methods: Magnetic resonance brain images were made prior to, and during, cross-sex hormone treatment to study the influence of anti-androgen + estrogen treatment on brain morphology in eight young adult male-to-female transsexual human subjects and of androgen treatment in six female-to-male transsexuals.

Results: Compared with controls, anti-androgen + estrogen treatment decreased brain volumes of male-to-female subjects towards female proportions, while androgen treatment in female-to-male subjects increased total brain and hypothalamus volumes towards male proportions.

Conclusions: The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain.

The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study Rametti et al Journal of Psychiatric Research, In Press, Corrected Proof, Available online 30 December 2010
Results
MtF transsexuals differed from both male and female controls bilaterally in the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract.
Conclusions
Our results show that the white matter microstructure pattern in untreated MtF transsexuals falls halfway between the pattern of male and female controls. The nature of these differences suggests that some fasciculi do not complete the masculinization process in MtF transsexuals during brain development.


Neuroimaging Differences in Spatial Cognition between Men and Male-to-Female Transsexuals Before and During Hormone Therapy
by Scoening et al J Sex Med. 2009 Sep 14.
Conclusions. Our results confirmed previously reported deviances of brain activation patterns in transsexual men (sic - these are MtoF) from men without GID and also corroborated these findings in a group of transsexual patients receiving cross-sex hormone therapy. The present study indicates that there are a priori differences between men and transsexual patients caused by different neurobiological processes or task-solving strategies and that these differences remain stable over the course of hormonal treatment.

Regional gray matter variation in male-to-female transsexualism. by Luders et al Neuroimage. 2009 Jul 15;46(4):904-7.
We analyzed MRI data of 24 male-to-female (MTF) transsexuals not yet treated with cross-sex hormones in order to determine whether gray matter volumes in MTF transsexuals more closely resemble people who share their biological sex (30 control men), or people who share their gender identity (30 control women). Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men. These findings provide new evidence that transsexualism is associated with distinct cerebral pattern, which supports the assumption that brain anatomy plays a role in gender identity.

Clinical Implications of the Organizational and Activational Effects of Hormones M.Diamond Hormones and Behavior 55 (2009) 621–632
The organization-activation theory posits that the nervous system of a developing fetus responds to prenatal androgens so that, at a postnatal time, it will determine how sexual behavior is manifest. How organization-activation was or was not considered among different groups and under which circumstances it is considered is basically understood from the research and comments of different investigators and clinicians. The preponderance of evidence seems to indicate that the theory of organization-activation for the development of sexual behavior is certain for non-human mammals and almost certain for humans.


Dichotic Listening, Handedness, Brain Organization and Transsexuality
Govier et al International Journal of Transgenderism, 12:144–154, 2010
This study investigated the functional brain organization of 68 male-to-female (MtF) transwomen and 26 female-to-male (FtM) transmen by comparing their performance with 36 typical male and 28 typical female controls on two indicators of cerebral lateralization: dichotic listening and handedness. A sex-differentiating dichotic test and a handedness questionnaire were administered. It was hypothesized that the MtF participants’ dichotic performance would be significantly different from the control males and resemble the control female pattern. This hypothesis was supported. It was also hypothesized that the FtM dichotic pattern would be significantly different from the control females and would resemble the control male pattern. This hypothesis was not supported. Finally, it was hypothesized that there would be significantly more nonexclusive right-handers in both trans-groups. This hypothesis was supported. Taken together, the dichotic and handedness data reported here indicate that the MtF and FtM conditions are not mirror images in terms of the verbal-auditory aspects of their brain organization and neurobiology plays an important role, particularly in the development of the male-to-female trans-condition.

Atypical Gender Development: a review Besser et al International Journal of Transgenderism 9(1): 29-44. 2006
44. In sum, gender identity, whether consistent or inconsistent with other sex characteristics, may be understood to be “much less a matter of choice and much more a matter of biology” (Coolidge et al., 2000). The scientific evidence supports the paradigm that transsexualism is strongly associated with the neurodevelopment of the brain (Zhou et al., 1995; Kruijver et al., 2000). It is clear that the condition cannot necessarily be overcome by “consistent psychological socialisation as male or female from very early childhood” and it is not responsive to psychological or psychiatric treatments alone (Green, 1999). It is understood that during the fetal period the brain is potentially subject to the organising properties of sex hormones (Kruijver et al., 2000; 2001; 2002; 2003). In the case of transsexualism, these effects appear to be atypical, resulting in sex-reversal in the structure of the BSTc, and possibly other, as yet unidentified, loci (Kruijver, 2004). The etiological pathways leading to this inconsistent development almost certainly vary from individual to individual, so no single route is likely to be identified. Different genetic, hormonal and environmental factors, acting separately or in combination with each other, are likely to be involved in influencing the development of the psychological identification as male or female. Psychosocial factors and cultural mores are likely to impact on outcomes (Connolly, 2003).

Biased-Interaction Theory of Psychosexual Development: “How Does One Know if One is Male or Female?” M.Diamond Sex Roles (2006) 55:589–600
A theory of gender development is presented that incorporates early biological factors that organize predispositions in temperament and attitudes. With activation of these factors a person interacts in society and comes to identify as male or female. The predispositions establish preferences and aversions the growing child compares with those of others. All individuals compare themselves with others deciding who they are like (same) and with whom are they different. These experiences and interpretations can then be said to determine how one comes to identify as male or female, man or woman. In retrospect, one can say the person has a gendered brain since it is the brain that structures the individual’s basic personality; first with inherent tendencies then with interactions coming from experience.

Specific Cerebral Activation due to Visual Erotic Stimuli in Male-to-Female Transsexuals Compared with Male and Female Controls: An fMRI Study by Gizewski et al J Sex Med 2009;6:440–448.
Results. Significantly enhanced activation for men compared with women was revealed in brain areas involved in erotic processing, i.e., the thalamus, the amygdala, and the orbitofrontal and insular cortex, whereas no specific activation for women was found. When comparing MTF transsexuals with male volunteers, activation patterns similar to female volunteers being compared with male volunteers were revealed. Sexual arousal was assessed using standard rating scales and did not differ significantly for the three groups.

Increased Cortical Thickness in Male-to-Female Transsexualism Luders et al, Journal of Behavioral and Brain Science, 2011

Abstract:
Results: Results revealed thicker cortices in MTF transsexuals, 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).
Conclusion: These findings provide further evidence that brain anatomy is associated with gender identity, where measures in MTF transsexuals appear to be shifted away from gender-congruent men.

Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Cohen-Kettenis PT. Arch Sex Behav. 2005 Aug;34(4):399-410.
Individuals with 5alpha-reductase-2 deficiency (5alpha-RD-2) and 17beta-hydroxysteroid dehydrogenase-3 deficiency (17beta-HSD-3) are often raised as girls. Over the past number of years, this policy has been challenged because many individuals with these conditions develop a male gender identity and make a gender role change after puberty. The findings also raised doubts regarding the hypothesis that children are psychosexually neutral at birth and emphasized the potential role of prenatal brain exposure to androgens in gender development. If prenatal exposure to androgens is a major contributor to gender identity development, one would expect that all, or nearly all, affected individuals, even when raised as girls, would develop a male gender identity and make a gender role switch later in life. However, an estimation of the prevalence of gender role changes, based on the current literature, shows that gender role changes occur frequently, but not invariably. Gender role changes were reported in 56-63% of cases with 5alpha-RD-2 and 39-64% of cases with 17beta-HSD-3 who were raised as girls. The changes were usually made in adolescence and early adulthood. In these two syndromes, the degree of external genital masculinization at birth does not seem to be related to gender role changes in a systematic way.

Prenatal exposure to testosterone and functional cerebral lateralization: a study in same-sex and opposite-sex twin girls. Cohen-Bendahan et al, Psychoneuroendocrinology. 2004 Aug;29(7):911-6.
In animals it has been shown that exposure to sex hormones is influenced by intrauterine position. Thus fetuses located between two male fetuses are exposed to higher levels of testosterone (T) than fetuses situated between two female fetuses or one female and one male fetus. In a group of opposite-sex (OS) twin girls and same-sex (SS) twin girls a potential effect of prenatal exposure to testosterone (T) on functional cerebral lateralization was investigated. We hypothesized that prenatal exposure to T would result in a more masculine, i.e. a more lateralized pattern of cerebral lateralization in OS twin girls than in SS twin girls. An auditory-verbal dichotic listening task (DLT) was used as an indirect method to study hemispheric specialization. Firstly, we established a sex difference on the DLT. Compared with SS girls, OS twin boys showed a more lateralized pattern of processing verbal stimuli. Secondly, as predicted OS girls had a more masculine pattern of cerebral lateralization, than SS girls. These findings support the notion of an influence of prenatal T on early brain organization in girls.

Prenatal exposure to diethylstilbestrol(DES) in males and gender-related disorders:results from a 5-year study Scott Kerlin. Proc. International Behavioral Development Symposium July 2005
More than 150 network members (out of 500) with “confirmed” or “strongly suspected” prenatal DES exposure identified as either “transsexual, pre- or post-operative,” (90 members), “transgender” (48 members), “gender dysphoric” (17 members), or “intersex” (3 members).
...
In this study, more than 150 individuals with confirmed or suspected prenatal DES exposure reported moderate to severe feelings of gender dysphoria across the lifespan. For most, these feelings had apparently been present since early childhood. The prevalence of a significant number of self-identified male-to-female transsexuals and transgendered individuals as well as some individuals who identify as intersex, androgynous, gay or bisexual males has inspired fresh investigation of historic theories about a possible biological/endocrine basis for psychosexual development in humans, including sexual orientation, core gender identity, and sexual identity (Benjamin, 1973; Cohen-Kettenis and Gooren, 1999; Diamond, 1965, 1996; Michel et al, 2001; Swaab, 2004).

Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones Sheri A. Berenbaum, Adriene M. Beltz Frontiers in Neuroendocrinology 32 (2011) 183–200
A key question concerns the extent to which sexual differentiation of human behavior is influenced by sex hormones present during sensitive periods of development (organizational effects), as occurs in other mammalian species. The most important sensitive period has been considered to be prenatal, but there is increasing attention to puberty as another organizational period, with the possibility of decreasing sensitivity to sex hormones across the pubertal transition. In this paper, we review evidence that sex hormones present during the prenatal and pubertal periods produce permanent changes to behavior.
There is good evidence that exposure to high levels of androgens during prenatal development results in masculinization of activity and occupational interests, sexual orientation, and some spatial abilities; prenatal androgens have a smaller effect on gender identity, and there is insufficient information about androgen effects on sex-linked behavior problems. There is little good evidence regarding long-lasting behavioral effects of pubertal hormones, but there is some suggestion that they influence gender identity and perhaps some sex-linked forms of psychopathology, and there are many opportunities to study this issue.

From Chapter 5 of The Transsexual Phenomenon by Harry Benjamin, 1966:
Another interesting observation, neither genetic nor endocrine, but nevertheless organic, was made some years ago by three American public health physicians, Drs. E. G. Williams, J. D. Reichard, and M. Pescor.[12] It concerned the reaction of the nervous system to Prostigmin, a rather powerful drug that acts directly on the nerves.

Normal males and females react alike. So do homosexual males. The drug, however, had no affect at all on the nerves of "feminine men." According to the authors, this may indicate a possible inborn physical trait having to do with an enzyme that takes part in the chemical reaction through which nerves stimulate muscular action.

To the best of my knowledge, these experiments have not been repeated as yet and therefore no confirmation or elaboration of the observation is available. In the light of the following paragraphs, however, they seem to gain particular significance.

Related to the genetic as well as the endocrine possibilities of etiology is a most recent one, coming from Williarn C. Young [13] and his group at the Oregon Regional Primate Research Center. It may be termed the neural or cerebroneural one. The neural structures and brain centers are the "target," that is to say, receiving organs for hormonal influences. Their genetic quality can decide how these hormones may affect them.

The Oregon group, working largely with monkeys, point to the "mechanism of hormonal action in organizing the tissues of the central nervous system." They say, "Evidence has accumulated indicating that the gonadal hormones have a broad role in the determination of (sex) behavior" through their "differentiation or organization of neural tissues."

[12] "Homosexuality: A Biological Anomaly," J. Nervous & Mental Diseases, Vol. 99, No. 65, January 1944.

[13] Young, William C., Goy, Robert W., Phoenix, Charles H., "Hormones and Sexual Behavior," Science, Vol. 143, No. 3603, January 17, 1964.
Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones Sheri A. Berenbaum, Adriene M. Beltz Frontiers in Neuroendocrinology 32 (2011) 183–200
A key question concerns the extent to which sexual differentiation of human behavior is influenced by sex hormones present during sensitive periods of development (organizational effects), as occurs in other mammalian species. The most important sensitive period has been considered to be prenatal, but there is increasing attention to puberty as another organizational period, with the possibility of decreasing sensitivity to sex hormones across the pubertal transition. In this paper, we review evidence that sex hormones present during the prenatal and pubertal periods produce permanent changes to behavior.
There is good evidence that exposure to high levels of androgens during prenatal development results in masculinization of activity and occupational interests, sexual orientation, and some spatial abilities; prenatal androgens have a smaller effect on gender identity, and there is insufficient information about androgen effects on sex-linked behavior problems. There is little good evidence regarding long-lasting behavioral effects of pubertal hormones, but there is some suggestion that they influence gender identity and perhaps some sex-linked forms of psychopathology, and there are many opportunities to study this issue.

The treatment of adolescent transsexuals: changing insights. Cohen-Ketternis et al, J Sex Med. 2008 Aug;5(8):1892-7.
Professionals who take responsibility for these youth and are willing to help should yet be fully aware of the impact of their interventions. In this article, the pros and cons of the various approaches to youngsters with GID are presented, hopefully inciting a sound scientific discussion of the issue.

Prenatal phthalate exposure and reduced masculine play in boys Swan et al, International Journal of Andrology, Volume 33, Issue 2, pages 259–269, April 2010
These data, although based on a small sample, suggest that prenatal exposure to antiandrogenic phthalates may be associated with less male-typical play behaviour in boys. Our findings suggest that these ubiquitous environmental chemicals have the potential to alter androgen-responsive brain development in humans.

Formally Unpublished Online Material

American Transman on "Male Gender Identity in an individual with Complete Androgen Insensitivity Syndrome"
Part 1 Part 2 Part 3 Part 4
In Part 1 of this series, we learned about O.J. Simpson. Oh, and also about the androgen receptor. We learned about its structure, what it does and how it is mutated, at least what we know at this point. (And prior to Part 1, I posted a link to a primer on Androgen Insensitivity Syndrome.)

In Part 2, the case was presented about a person who was born with unremarkable female genitalia and was raised female but who reported a male gender identity in adulthood (T’Sjoen et al., 2010). No big deal, right? This description could be about me and plenty of other guys. The significance is that this person is a chromosomal male with a mutated androgen receptor gene and so has Complete Androgen Insensitivity Syndrome (CAIS). In other words, his body cannot recognize or respond to the testosterone that his internalized testes produce.

This case of an individual with CAIS goes against the theory that testosterone masculinizes the brain during fetal development to result in male gender identity. According to the theory, without a functional androgen receptor, a person should not be able to have a male gender identity, no matter what their chromosomal makeup.

And that led us to Part 3, where we talked about gender-typical behavior and gender identity of chromosomal females with the intersex condition of Congenital Adrenal Hyperplasia. CAH is typified by excess androgen production during fetal development due to genetic mutations affecting the steroidogenic pathways of the adrenal glands.

In discussing 46,XX individuals with CAH, the reasoning was that if excess androgens such as testosterone were present in sufficient quantity to virilize the developing genitalia, then the masculinization of the brain should also have occurred. The studies we discussed were designed to test the assumption that masculinization of the genitalia in 46,XX individuals with CAH was correlated with masculinization of the brain, as evidenced by masculine-typical behavior and male gender identity. The problem with this reasoning was, as we learned, that there is no proof that the degree of genital virilization in individuals with CAH correlates with the amount of testosterone present.


Brain gender identity
. SW Ecker. Abstract presented at the American Psychiatric Association Annual Meeting; May 18, 2009; San Francisco.
Gender Identity is that innate sense of who you are in this world with reference to your sexuality and behavior, not necessarily corresponding to your genitalia and reproductive organs. Transgenders are atypical and “think” as the opposite gender. Certain areas of the brain have been shown to be sexually dimorphic. They are different in structure and numbers of neurons in males versus females. Protein Receptors for the sex hormones in different areas of the brain (limbic and anterior hypothalamic) must be present in sufficient numbers to receive those powerful hormones. There are androgen receptors (AR), Estrogen Receptors (ER), and Progesterone receptors (PRs). ARs or ERs are predominant at different times in different parts of the human brain. Hormone receptor genes have been identified in humans, which are responsible for sexually dimorphic brain differentiation in the hypothalamus. The groundwork in brain gender identity is gene-directed and takes place by forming male and female hormone receptors in the brain before the gonads and hormones can influence them. Multiple genes acting in concert determine our sexual identity. The human brain continues to make neurons and synaptic neuronal connections throughout life. This contributes to Gender Role Behaviors making individuals in the continuum of gender identity. Gender behaviors must be differentiated from gender identity (Hines). Gender Identity cannot be predicted from anatomy (Reiner). Brain gender identity is determined very early in fetal development, but gender expression, expressed as behaviors requires hormonal, environmental, social and cultural interactions, which evolve with time. One cannot deny the profound effects of Testosterone, Estradiol and other steroids on genital differentiation in-utero or their effects on behavior from birth or the physical and mental cross gender changes caused by exogenous hormones, but gender identity is determined before and persists in spite of these effects.
Associated Presentation.


Bigender and the Brain
ZE Brain AEBrain(2008)

Dr Veronica Drantz' Presentations : Disordered or Just Different Others

The Transsexual Phenomenon H.Benjamin

Sex Reassignment. Thirty Years of International Follow-up Studies After Sex Reassignment Surgery: A Comprehensive Review, 1961-1991 Friedemann Pfäfflin, Astrid Junge (Translated from German into American English by Roberta B. Jacobson and Alf B. Meier)


Current Thinking on the Etiology of Gender Dysphoria Reprinted from The Gendered Self--Further commentary on the transsexual phenomenon by Anne Vitale PhD (2010, pp 13-16)
There is no clearly understood cause for gender variance. However, we have enough information about fetal brain development and the procedure the embryo goes through in becoming either male, female or intersexed, to implicate the complexity of the procedure itself as a cause of the spontaneous sex reversal or potential sex/gender discontinuity (1). What follows is an abbreviated sample of what we now know about what goes on relative to being gendered physiologically.
Even though the brain has both androgen and estrogen receptors, the male brain has been found to be markedly different from the female brain. Not only is the male brain larger and more capable of spatial perception, researchers studying the brains of male and female rats have found evidence that prior to being masculinized, the genetic male brain must first be defeminized,(4-7) a process by which males lose the ability to display female-type behavior.
Once in the fetal brain, testosterone is either metabolized into dihydrotestosterone by an enzyme named 5 alpha reductase or converted to estradiol by an enzyme called aromatase. Counterintuitively, increased estrogen receptor activation is responsible for defeminization while increased androgen receptor activation seems to be responsible for masculinization.(8,9) All this makes clear that there is nothing straightforward about an individual being born with a gender identity that matches their biological sex.
This leads one to consider the possibility that male hormonal surges must occur not only in sufficient amounts in the developing fetus, but must be timed to take advantage of the short time the brain is open to being defeminized/masculinized, forming a predominantly male gendermap. If there is insufficient androgen, or the surge comes too late, the gendermap may be only partially imprinted as male. These disruptions of hormonal surges may come from a variety of sources, including a disorder in the mother's endocrine system such as a hormone-secreting tumor, common maternal stress, medications or some other toxic substance or adverse event yet to be identified.
Being the default condition, genderizing the genetic female brain is far less complex but still subject to having something stray from the norm. If nothing untoward happens, the brain remains female and the individual feels no dis-ease with her body. However, there remains the possibility of a defeminizing/masculinization event to occur for both sexes in utero.
Gender identity, far from being absolute, appears to occur on a continuum, with most people gathered at either end, the rest being somewhere in between. Feelings of discomfort or complete inappropriateness about one's assigned sex do not mean the individual is wrong or ill. It simply means that the assignment made at birth almost universally on the shape of one's genitals can, on occasion, differ from the unseen brain imprint.


Potential Therapeutic Errors When Using Binary Based Terminology to Explain the Gender Variant Condition Anne Vitale Ph.D. November 11, 2006
Secondly, “Dysphoria,” defined by Marriam-Webster’s Collegiate dictionary as “a state of feeling unwell or unhappy,” or in the American College Dictionary as “a state of dissatisfaction, anxiety, restlessness, or fidgeting” is simply too soft a word to describe the angst most clinicians see on intake with this population. At best it may be an apt descriptor for individuals who, despite strong evidence to the contrary, are making an extraordinary effort to convince themselves that they are sex/gender congruent. These individuals make life decisions such as getting married and having children not only because they may find it appealing to have a spouse and have children but with the added hope that this activity will ease or erase their obsessive cross gender thoughts. Although there may be instances where these special efforts succeed, (i.e. the incongruity is mild) the more likely outcome is a realization they have actually made matters worse. Typically, at time of presentation these individuals report that either their lives are in ruin, or they are very afraid that if their gender variant condition was to become known they would loose all that they cherish and be ostracized from family, friends and the ability to support themselves. High anxiety and deep depression with concurrent suicide ideation is common. One of the most extreme cases I have treated was that of a 50 year old genetic male, married and the father of 3 grown children with an international reputation as a scientist who reported to me that the reason he finally sought out treatment for his gender issues was because the number of times he found himself curled up in the corner of his office in the fetal position muffling his cry was increasing. That is not dysphoria, that is pure misery.

Gender Differences in Human Brain: A Review Z.F Zaidi The Open Anatomy Journal, 2010, 2, 37-55
CONCLUSION The male and the female brains show anatomical, functional and biochemical differences in all stages of life. These differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual...