in relation to gender identity
Copyright @ 2009, HBS International
Dr. Swaab, Dick F and Dr. Alicia Garcia-Falgueras
CIC Edizioni Internatzionaly 2009
All Rights Reserved
Functional Neurology. September 2009.
During the intrauterine
period the fetal brain develops 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) is programmed 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 transsexualism.
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 proof that social environment after birth has an effect on gender
Sexual organization and activation of the human brain
The process of sexual
differentiation of the brain brings about permanent changes in brain structures and functions via interactions of the developing
neurons with the environment, understood in its widest sense. The environment of a developing neuron is formed by the surrounding
nerve cells and the child's circulating hormones, as well as the hormones, nutrients, medication and other chemical substances
from the mother and the environment that enter the fetal circulation via the placenta. All these factors may have a lasting
effect on the sexual differentiation of the brain.
The testicles and
ovaries develop in the sixth week of pregnancy. This occurs under the influence of a cascade of genes, starting with the sex-determining
gene on the Y chromosome (SRY). The production of testosterone by a boy's testes is necessary for sexual differentiation of
the sexual organs between weeks 6 and 12 of pregnancy. The peripheral conversion of testosterone into dihydrotestosterone
is essential for the formation of a boy's penis, prostate and scrotum. Instead, the development of the female sexual organs
in the womb is based primarily on the absence of androgens (1).
Once the differentiation
of the sexual organs into male or female is settled, the next thing that is differentiated is the brain, under the influence,
mainly, of sex hormones on the developing brain cells. The changes (permanent) brought about in this stage have organizing
effects; later, during puberty, the brain circuits that developed in the womb are activated by sex hormones. This paradigm
of sexual differentiation of the brain has been well established, ever since the first paper by Phoenix et al. (2).
The fetal brain
is protected against the effect of circulating estrogens from the mother by the protein alpha-fetoprotein, which is produced
by the fetus and binds strongly to estrogens but not to testosterone (3,4). However, estrogens do not only reach the brain
via circulation: the brain itself is also capable of producing estrogens. In human beings testosterone may thus not only have
a direct effect on a masculine brain, but, once converted into estrogens by aromatase, may also act on developing neurons.
In addition, there are sex differences in brain steroid receptor distribution not only in adulthood (5-8) but also during
development (9). In rats, the formation of estradiol in the brain by aromatization of circulating testosterone is the most
important mechanism for virilization of the brain (10), but, as seen below, it does not determine human gender identity. There
may also be direct genetic effects that affect the sexual differentiation of the brain without involving the sex hormone receptors.
Some fetal rat brain cells undergo sexual differentiation, even in tissue culture, without the involvement of sex hormones
The genes SRY and ZRY are candidates for this action since they are expressed until very advanced ages in
the human brain, even though strictly speaking the role of these genes in sexual differentiation stops during development
(13,14). There are at present many additional candidate genes for a role in sexual differentiation of the brain without the
involvement of hormones, since it has been found that fifty genes are expressed at different levels in the brains of male
and female mouse fetuses, even before the hormones come into play (15). Also, genes that escape inactivation on the X chromosome
(such as PCDH11X) could show sexually dimorphic expression and thus contribute to sexually dimorphic functions (16). Thus,
the sexual differentiation of the brain is not caused by hormones alone, even though they are very important for gender identity.
Sex hormones and human brain development
During fetal development,
the brain is influenced by sex hormones such as testosterone, estrogens and progesterone (17). From the earliest stages of
fetal brain development, many neurons throughout the entire nervous system already have receptors for these hormones (9).
The early development of boys shows two periods during which testosterone levels are known to be high. The first surge
occurs during mid-pregnancy: testosterone levels peak in the fetal serum between weeks 12 and 18 of pregnancy (18) and in
weeks 34-41 of pregnancy the testosterone levels of boys are ten times higher than those of girls (19). The second surge takes
place in the first three months after birth. At the end of pregnancy, when the alpha-fetoprotein level declines, the fetus
is more exposed to estrogens from the placenta, this exposure inhibiting the hypothalamus-hypophysial-gonadal axis of the
developing child. Loss of this inhibition once the child is born causes a peak in testosterone in boys and a peak in estrogens
in girls (20). The testosterone level in boys at this time is as high as it will be in adulthood, although a large part of
the hormone circulates bound.
During these two periods, therefore, girls do not show high levels of testosterone.
These fetal and neonatal peaks of testosterone, together with the functional steroid receptor activity, are thought to fix
the development of structures and circuits in the brain for the rest of a boy's life (producing "programming" or "organizing"
effects). Later, the rising hormone levels that occur during puberty "activate" circuits and behavioral patterns that were
built during development, in a masculinized and de-feminized direction for male brains or in a feminized and de-masculinized
direction for female brains.
The brain structure differences that result from the interaction between hormones and developing
brain cells are thought to be the basis of sex differences in a wide spectrum of behaviors, such as gender role (behaving
as a man or a woman in society), gender identity (the conviction of belonging to the male or female gender), and sex differences
regarding cognition, aggressive behavior and language organization. Factors that interfere with the interactions between hormones
and the developing brain systems during development in the womb may permanently influence later behavior.
differentiation of the genitals takes places much earlier in development (i.e. in the first two months of pregnancy) than
sexual differentiation of the brain, which starts in the second half of pregnancy and becomes overt upon reaching adulthood,
these two processes may be influenced independently of each other. In rare cases, this may result in transsexualism, i.e.
people with male sexual organs who feel female or vice versa. It also means that in the event of an ambiguous sex at birth,
the degree of masculinization of the genitals may not always reflect the degree of masculinization of the brain (21-24).
addition, gender identity may be determined by prenatal hormonal influences, even though the prenatal hormonal milieu might
be inadequate for full genital differentiation (25).
Programmed gender identity is irreversible
of programmed gender identity is clearly illustrated by the sad story of the John-Joan-John case (the case of David Reimer). In the 1960s and 1970s, in the context of the concept of behaviorism, it was postulated that a child is born as a tabula
rasa and is subsequently forced in the male or female direction by society's conventions.
Although it is true that,
in humans, self-face recognition appears to emerge at around 18 months of age (26) and that by the age of 2- 3 years children
are able to correctly label themselves and others according to gender (27), there is no evidence that external or social events
might modify these processes. However, J. Money argued that: "Gender identity is sufficiently incompletely differentiated
at birth as to permit successful assignment of a genetic male as a girl. Gender identity then differentiates in keeping with
the experiences of rearing" (28). This view had devastating results in the John-Joan-John case (29).
that gender imprinting does not start until the age of 1 year, and that its development is well advanced by the age of 3-4
years (30). This was, indeed, the basis for the decision to make a girl out of an 8-month-old boy who lost his penis due to
a mistake during minor surgery (i.e. an operation to correct phimosis). The testicles of this child were removed before he
reached the age of 17 months in order to facilitate feminization. The child was dressed in girls' clothes, received psychological
counseling and was given estrogens in puberty.
According to Money, this child developed as a normal female. However,
Milton Diamond later made it clear that this had not been the case at all. In adulthood, this child changed back to male,
married, and adopted several children (31). Unfortunately, he had a troubled life and committed suicide in May 2004.
story illustrates the enormous programming influence of the intrauterine period on gender. Other cases have been described
in the literature (32), due to enzymatic disorders (33-35) or to cloacal exstrophy (36), that support the existence of early
permanent programming of brain sex by biological factors and androgen exposure, rather than by social environment and learning
The mechanism of sexual differentiation of the brain: neurobiological factors
In male rats, testosterone
is turned into estrogens by local aromatization in the brain, and these estrogens then masculinize certain brain areas. This
finding agrees with the observation that in partially androgen insensitive (testosterone feminized - Tfm) male rats no reversion
of the sex difference was present in the preoptic area (10) and the bed nucleus of the stria terminalis (38).
animals retained a male neuroanatomy. Other brain nuclei, such as the posteromedial amygdala, the ventromedial hypothalamus
and the locus coeruleus were, however, feminized in Tfm male rats (38-40).
In humans, however, the main mechanism
appears to involve a direct effect of testosterone on the developing brain. Complete androgen insensitivity syndrome is caused
by mutations in the receptor gene for androgens. Despite their genetic (XY) masculinity, affected individuals develop as phenotypical
women without gender problems (41).
On the other hand, when a boy fetus has a 5-alpha-reductase-2 or 17s-hydroxy-steroid
dehydrogenase-3 deficiency preventing peripheral testosterone from being transformed into dihydrotestosterone, a girl? with a large clitoris is born.
These children are generally raised as girls. However, when testosterone production increases in these XY children during
puberty, this clitoris? grows to penis size, the testicles descend, and the child build begins to masculinize and become muscular.
Despite the fact that these children are initially raised as girls, the majority of them (60%) change into heterosexual males
(24,34,35,42,43), apparently due to the organizing effect of testosterone on early brain development. Boys who are born with
a cloacal exstrophy, i.e. with bladder exstrophy and a partly or wholly absent penis are usually changed into girls immediately
A survey showed that in adulthood only 65% of these children who were changed into girls continued to
live as girls, and when individuals with gender identity disorder were excluded the figure dropped to 47% (44,45).
From these examples it appears that the direct action of testosterone on the developing brain in boys and the lack
of it in the developing brain in girls are crucial factors in the development of male and female gender identity, although
other sexually dimorphic functions still need to be investigated in these people.
Conversely, studies on cloacal exstrophy
suggest that the postnatal testosterone peak is not crucial for gender identity development, given that these children generally
undergo operation shortly after birth.
Sex differences in the human brain
A sex difference
in brain weight is already present in children from the age of 2 years (46) and sex differences can thus be expected throughout
the brain from early in development. In the adult human brain structural sex differences can be found from the macroscopic
level (47) down to the ultramicroscopic level (48).
When observed by our group, the structural
difference in the intermediate nucleus of the human hypothalamus (InM) (60-62) was at first termed the sexually dimorphic
nucleus of the preoptic area (SDN-POA) (63). We found this nucleus to be 2.5 times larger in men than in women and to contain
2.2 times as many cells (63). Allen et al., (64) described four interstitial nuclei of the anterior hypothalamus (INAH1-4)
and found, in men compared to women, a larger volume of the INAH3 and INAH2 subdivisions (respectively 2.8 and 2 times greater).
The fact that they could not find a sex difference in INAH1 (= SDN-POA), as found by us (63), could be fully explained by
the strong age effect on the sex differences of this nucleus (58,65).
Functionally, too, a large number of sex differences in different
brain regions have recently been described (49-53). Sexual differentiation of the human brain is also expressed in behavioral
differences, including gender identity (22, 54-57), and in differences at the level of brain physiology and in the prevalence
of neurological and psychiatric disorders (57-59). In the current review we focus on the sex differences in the human hypothalamus
and adjacent areas.
In fact, the sex difference develops only after
the age of 5 years and disappears temporarily after the age of 50 years (63,66,67). Moreover, it is now clear that what we
called the SDNPOA (63) is actually a horseshoe-shaped structure that can show up in sections as two separate nuclei (58,62),
which Allen et al., (64) called INAH1 and 2, or as just one nucleus, called the intermediate nucleus (62) or SDN-POA (63).
Further analysis of INAH1 and 2 in persons with transsexualism is ongoing, and confirms the presence of a clear
sex difference in adult controls up to 50 years of age.
We recently localized and delineated
the uncinate nucleus (Un) using three different stainings, i.e. thionin, neuropeptide-Y and synaptophysin. We found sex differences
in volume and neuron number in the INAH3 subdivision while no differences were found for INAH4 (68, Fig. 1). The INAH3 volume
size and the presence of a sex difference in INAH3 volume size fully agreed with previously reported data (54,64,69,70), as
did the sex difference for the number of neurons in INAH3. A number of different names have been used to refer to the two
Un subnuclei (68): i) periventricular and uncinate nucleus (the former closer to the third ventricle than the latter) (61);
ii) INAH4 (closer to the third ventricle than the INAH3) (64); and, most recently, iii) lateral and medial subdivisions of
the Un (62).
In view of the evidence provided by neurochemical markers such as neuropeptide- Y and synaptophysin,
and the fact that they appear as one structure in some subjects, there are indeed arguments in favor of considering these
two subdivisions a single structure called the Un. Koutcherov et al. also suggested that the Un was the homolog of the rat
central subdivision of the medial preoptic nucleus (MPOc) (62) that, in this animal, is clearly related to the brain network
for input and output of male sexual behavior (17,71).
Moreover, INAH3 was found in (XY) women with transsexualism to
be small (of female size and cell number), while the INAH4 subdivision did not show gender-related differences, morphological
or otherwise, between men and women (68; Fig. 1). In addition, sex differences were found in the INAH3 volume as delineated
by neuropeptide Y, but not in INAH4.
Other sex differences have been found in the human anterior
commissure, the interthalamic adhesion and in the corpora mamillaria (58,72).
Sex hormone receptors and neurosteroids
Sex hormone receptors,
too, are expressed in a sexually dimorphic way in the human hypothalamus and adjacent areas.
In most hypothalamic areas that show
androgen receptor (AR) staining, nuclear staining, in particular, is less intense in women than in men. The strongest sex
difference was found in the lateral and the medial mamillary nucleus (MMN; 73). The mamillary body complex is known to be
involved in several aspects of sexual behavior, such as arousal of sexual interest and penile erection (58,73,74).
addition, a sex difference in AR staining was present in the horizontal diagonal band of Broca, SDN-POA, medial preoptic area
(MPO), dorsal and ventral zone of the periventricular nucleus (PVN), supraoptic nucleus (SON), ventromedial hypothalamic nucleus,
and infundibular nucleus (INF).
However, no sex differences were observed in AR staining in the adult bed nucleus
of the stria terminalis (BST), the nucleus basalis of Meynert, and the islands of Calleja (73). A female-like pattern was
found in 26- and 53-year-old castrated men and in intact old men. These data indicate that the amount of nuclear receptor
staining in the adult mamillary complex is dependent on the circulating levels of androgens rather than on gender identity.
This idea is supported by the fact that a male-like pattern of AR staining was found in a 36-year-old non-castrated women
with transsexualism (T6) and a heterosexual virilized woman aged 46 (5), while a female-like pattern for INAH3 volume
and number of cells was found in the former patient (T6) (68).
Various sex differences
have been observed for estrogen receptor alpha (ER-alpha) staining in the hypothalamus and adjacent areas of young adult
human subjects. More intense nuclear ER-alpha immunoreactivity was found in young men compared with young women, for example,
in the SDN-POA, the SON, and the PVN. Women showed a stronger nuclear ER-alpha immunoreactivity in the suprachiasmatic nucleus
(SCN) and MMN. No sex differences in nuclear ER-alpha staining were found in, for example, the central subdivision of the
bed nucleus of the stria terminalis (BSTc), the islands of Calleja, or in the INF. More intense nuclear ER-alpha staining
was found in men, for example, in neurons of the BSTc, the islands of Calleja, and the SDN-POA. Women showed more nuclear
ER-alpha staining in the SCN, the SON, the PVN, the INF and the MMN (75).
Observations in subjects with abnormal hormone
levels showed, in most areas, ER-alpha immunoreactivity distribution patterns that were consistent with the level of circulating
estrogens, suggesting that the majority of the reported sex differences in ER-alpha immunoreactivity are "activational" rather
than "organizational" in nature (76, 77).
In the BSTc, differences in sex hormone receptors such as ER-alpha, ER-beta,
the AR and progesterone receptor (PR), are present from fetal age onward. More nuclear estrogen receptors were observed
in females than in males during the fetal/neonatal ages, whereas there were no overt sex differences in the other three sex
hormone receptors detected. In adult men ER and PR immunoreactivity was more pronounced in the BSTc of men than in women (9).
Hence, the sensitivity of the BSTc for the different sex hormones depends strongly on sex and age.
(Harry Benjamin Syndrome)
There is a vast
array of factors that may lead to gender problems. Twin and family research has shown that genetic factors play a part (78,79).
Rare chromosomal abnormalities may lead to transsexualism (80), and it was recently found that polymorphisms of the genes
for ER-alpha and ER-beta, AR repeat length polymorphism, and polymorphisms in the aromatase or CYP17 gene also produced an
increased risk (79,81,82).
levels during early development may play a role, as suggested by the high frequency of polycystic ovaries, oligomenorrhea
and amenorrhea in (XX) men with transsexualism. This observation suggests early intrauterine exposure of the female fetus
to abnormally high levels of testosterone (83). A recent study did not confirm a significantly increased prevalence of polycystic
ovary syndrome. However, there was a significantly higher prevalence of hyperandrogynism in men with transsexualism, also
indicating the possible involvement of high testosterone levels in transsexualism (84). A girl with congenital adrenal hyperplasia
(CAH), who has been exposed to extreme levels of testosterone in utero, will also have an increased chance becoming a form
Although the likelihood of transsexualism developing in such cases is 300-1000 greater than normal,
the risk for transsexualism in CAH is still only 1-3% (85), whereas the probability of serious gender problems is 5.2% (86).
The consensus is, therefore, that girls with CAH should be raised as girls, even when they are masculinized (24).
who were given phenobarbital or diphantoin during pregnancy have an increased risk of giving birth to a child with transsexualism
(Harry Benjamin Syndrome). Both these substances change the metabolism of the sex hormones and can act on the sexual differentiation of the child's
brain. In a group of 243 women who had been exposed to such substances during pregnancy, Dessens et al. (87) found three children
with Harry Benjamin Syndrome, these are relatively high rates for such a rare condition. On the "DES sons" (diethylstilbestrol,
an estrogen-like substance - see later) website they claim that Harry Benjamin Syndrome occurs in 35.5% of the DES
cases (88,89). This is alarming, but needs, of course, to be confirmed in a formal study.
There are no indications
that postnatal social factors could be responsible for the occurrence of Harry Benjamin Syndrome (90). Only in 23%
of cases does a childhood gender problem lead to Harry Benjamin Syndrome in adulthood.
Harry Benjamin Syndrome and the brain
The theory on the
origins of Harry Benjamin Syndrome is based on the fact that the differentiation of sexual organs takes place during
the first couple of months of pregnancy, before the sexual differentiation of the brain.
We found a clear sex difference in
the human BSTc and INAH3. In men the BSTc area was twice that found in women and contained twice as many somatostatin neurons
(94,95). The same was true of the INAH3, which was found to be 1.9 times larger in men than in women and to contain 2.3 times
as many neurons (68; Fig. 1). In (XY) women with Harry Benjamin Syndrome we found a completely female BSTc
and INAH3. Until now we have only been able to obtain material from one (XX) man with Harry Benjamin Syndrome, and his BSTc
and INAH3 indeed turned out to have all the male characteristics. We were able to exclude the possibility that the reversal
of sex differences in the BSTc and INAH3 were caused by changing hormone levels in adulthood (68,94,95), and it therefore
seems that we are dealing with a developmental effect.
As these two processes have
different timetables, it is possible, in principle, that they take different routes under the influence of different factors.
If this is the case, one might expect to find, in people with Harry Benjamin Syndrome, female structures in a male brain and
vice versa, and indeed, we did find such reversals in the central nucleus of the BSTc and in the INAH3, two brain structures
that, in rats, are involved in many aspects of sexual behavior (17,58).
Our observations thus support the above-mentioned neurobiological
theory about the origin of Harry Benjamin Syndrome. The size of the BSTc and the INAH3 and their number of neurons match the
gender that persons with HBS feel they belong to, and not the sex of their sexual organs, birth certificate
or passport. Unfortunately, the sex difference in the BSTc volume does not become apparent until early adulthood (96), meaning
that this nucleus cannot be used for early diagnosis of Harry Benjamin Syndrome.
In women with Harry Benjamin Syndrome
(HBS) who receive hormonal treatment, some intermediate values, between those typical for men and women, have been found
for lateralization and cognitive performance (90). Recently, functional reversals have been reported in the brains of HBS
A functional magnetic resonance imaging (fMRI) study in women with HBS, who were not treated hormonally,
showed that a number of brain areas in the HBS-related section of the hypothalamus were activated by pheromones
in a sex-atypical way. Although the functional reactions in the hypothalamus to an estrogen-derived pheromone were predominantly
female, women with Harry Benjamin Syndrome also showed some characteristics of a male activation pattern (97). When viewing
erotic stimuli, women with HBS before treatment tended to display female-like cerebral processing on fMRI (98).
The human fetal
brain develops in the male direction through a direct action of testosterone and in the female direction through the absence
of this hormone. During the intrauterine period, gender identity (the conviction of belonging to the male or female gender),
cognition, aggression and other behaviors are programmed in the brain in a sexually differentiated way. The differences observed in the INAH3
in relation to gender identity and this structure's possible connection with the BSTc suggest that these two nuclei and the
two earlier described nuclei that were found to be related to gender identity, i.e. the SDN-POA (= intermediate nucleus =
INAH1 and 2) and SCN, are all part of a complex network involved in various aspects of gender identity.
of the genitals takes place in the first two months of pregnancy, whereas sexual differentiation of the brain starts in the
second half of pregnancy. This means that in the event of an ambiguous sex at birth, the degree of masculinization of the
genitals may not reflect the degree of masculinization of the brain.
Our observations on reversed sex differences
in the brains of patients with transsexualism (Harry Benjamin Syndrome) support the idea that HBS is based
on an opposite sexual differentiation of i) sexual organs during the first couple of months of pregnancy and ii) the brain
in the second half of pregnancy.
There is no proof that the social environment after birth has an effect on the development
of gender identity, while the possible effects on sexual differentiation of the brain by endocrine disrupters in the environment
and in medicines given to the pregnant mother should be investigated.
research on gender identity in humans is only just gathering momentum, but the evidence shows that humans have a vast array
of brain differences related to gender. There is a need for further multidisciplinary research on the putative influence of
testosterone in development, e.g. in individuals with complete androgen-insensitivity syndrome.
We thank Bart Fisser,
Unga Unmehopa, Rawien Balesar, Arja A. Sluiter, Joop Van Heerikhuize and Ton Puts for their technical help, Wilma Verweij
for her secretarial help, Jenneke Kruisbrink for her literature resource help and Mrs Terry Reed, Dr Michel Hofman and Dr
Ronald W.H. Verwer for their critical comments. Brain material was provided by the Netherlands Brain Bank (coordinator Dr
Inge Huitinga). Financial support was obtained from CajaMadrid Bank, from GIRES and Mermaids and from the Netherlands Institute
1. Swaab DF, Chung
WC, Kruijver FP, Hofman MA, Hestiantoro A. Sex differences in the hypothalamus in the different stages of human life. Neurobiol
2. Phoenix CH, Goy
RW, Gerall AA, Young WC. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating
behaviour in the female guinea pig. Endocrinology 1959;65:369-382
3. Bakker J, De
Mees C, Douhard Q et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization
by estrogens. Nat Neurosci 2006;9:220-226
4. Bakker J, Baum
MJ. Role for estradiol in female-typical brain and behavioral sexual differentiation. Front Neuroendocrinol 2008;29:1-16
5. Kruijver FP,
Fernandez-Guasti A, Fodor M, Kraan EM, Swaab DF. Sex differences in androgen receptors of the human mamillary bodies are related
to endocrine status rather than to sexual orientation or transsexuality. J Clin Endocrinol Metab 2001;86:818-827
6. Swaab DF, Chung
WC, Kruijver FP, Hofman MA, Ishunina TA. Structural and functional sex differences in the human hypothalamus. Horm Behav 2001;40:93-98
7. Kruijver FP,
Swaab DF. Sex hormone receptors are present in the human suprachiasmatic nucleus. Neuroendocrinology 2002;75:296-305
8. Ishunina TA,
Swaab DF. Estrogen receptor-alpha splice variants in the human brain. Gynecol Endocrinol 2008;24: 93-98
9. Chung WCJ. Doctoral
Thesis: Sexual differentiation of the human and rodent forebrain: gonadal steroid receptors and apoptosis in the bed nucleus
of the stria terminalis and medial preoptic nucleus. The Netherlands Institute for Neuroscience, University of Amsterdam,
January 15th 2003
10. Gorski RA. Critical
role for the medial preoptic area in the sexual differentiation of the brain. Prog Brain Res 1984; 61:129-146
11. Reisert I, Pilgrim
C. Sexual differentiation of monoaminergic neurons-genetic or epigenetic? Trends Neurosci 1991;14: 468-473
12. Davies W, Wilkinson
LS. It is not all hormones: alternative explanations for sexual differentiation of the brain. Brain Res 2006; 1126: 36-45
13. Mayer A, Lahr
G, Swaab DF, Pilgrim C, Reisert I. The Ychromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics
14. Bocklandt S,
Vilain E. Sex differences in brain and behavior: hormones versus genes. Adv Genet 2007;59:245-266
15. Dewing P, Shi
T, Horvath S, Vilain E. Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res Mol
Brain Res 2003;118:82-90
16. Lopes AM, Ross
N, Close J, Dagnall A, Amorim A, Crow TJ. Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in
brain. Hum Genet 2006;119:267- 275
17. Swaab DF. The
human hypothalamus. Basic and clinical aspects. Part II: Neuropathology of the hypothalamus and adjacent brain structures.
In: Aminoff MJ, Boller F, Swaab DF eds Handbook of Clinical Neurology. Amsterdam; Elsevier 2004:193-231
18. Finegan JA,
Bartleman B, Wong PY. A window for the study of prenatal sex hormone influences on postnatal development. J Genet Psychol
19. De Zegher F,
Devlieger H, Veldhuis JD. Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day
of birth. Pediatric Res 1992;32:605-607
20. Quigley CA.
Editorial: The postnatal gonadotropin and sex steroid surge-insights from the androgen insensitivity syndrome. J Clin Endocrinol
21. Swaab DF. Sexual
differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation. Gynecol Endocrinol
22. Swaab DF. Sexual
diffentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab 2007;21:431-444
23. Swaab DF. Sexual
orientation and its basis in brain structure and function. Proc Natl Acad Sci U S A 2008;105: 10273- 10274
24. Hughes IA, Houk
C, Ahmed SF et al. Consensus statement on management of intersex disorders. Arch Dis Child 2006;91:554-563
25. Reiner WG. Assignment
of sex in neonates with ambiguous genitalia. Curr Opin Pediatr 1999;11:363-365
26. Keenan JP, Wheeler
MA, Gallup GG Jr, Pascual-Leone A. Self-recognition and the right prefrontal cortex. Trends Cogn Sci 2000;4:338-344
27. Ahmed SF, Morrison
S, Hughes IA. Intersex and gender assignment; the third way? Arch Dis Child 2004;89:847-850
28. Money J. Ablatio
penis: normal male infant sex-reassigned as a girl. Arch Sex Behav 1975;4:65-71
29. Colapinto J.
As Nature Made Him. The Boy Who was Raised as a Girl. New York; Harper Collins Publishers Inc 2001
30. Money J, Erhardt
AA. Man and Woman, Boy and Girl: The Differentiation and Dimorphism of Gender Identity from Conception to Maturity. Baltimore;
Johns Hopkins University Press 1972
31. Diamond M, Sigmundson
K. Sex reassignment at birth. Long-term review and clinical implications. Arch Pediatr Adolesc Med 1997;151:298-304
32. Bradley SJ,
Oliver GD, Chernick AB, Zucker KJ. Experiment of nurture: ablatio penis at 2 months, sex reassignment at 7 months, and a psychosexual
follow-up in young adulthood. Pediatrics 1998;102:e9
33. al-Attia HM.
Gender identity and role in a pedigree of Arabs with intersex due to 5alpha reductase-2 deficiency. Psychoneuroendocrinology1996;
PT. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency.
Arch Sex Behav 2005;34: 399-410
35. Praveen EP,
Desai AK, Khurana ML et al. Gender identity of children and young adults with 5alpha-reductase deficiency. J Pediatr Endocrinol
36. Reiner WG. Gender
identity and sex-of-rearing in children with disorders of sexual differentiation. J Pediatr Endocrinol Metab 2005;18:549-553
37. Jorgensen M,
Hiort O, Holterhus PM, Thyen U. Gender role behavior in children with XY karyotype and disorders of sex development. Horm
A, Pinos H, Collado P et al. The role of the androgen receptor in CNS masculinization. Brain Res 2005; 1035:13-23
39. Morris JA, Jordan
CL, Dugger BN, Breedlove SM. Partial demasculinization of several brain regions in adult male (XY) rats with a dysfunctional
androgen receptor gene. J Comp Neurol 2005;487:217-226
40. Zuloaga DG,
Puts DA, Jordan CL, Breedlove SM. The role of androgen receptors in the masculinization of brain and behavior: what we've
learned from the testicular feminization mutation. Horm Behav 2008;53:613-626
41. Wisniewski AB,
Migeon CJ, Meyer-Bahlburg HF et al. Complete androgen insensitivity syndrome: long term medical, surgical, and psychosexual
outcome. J Clin Endocrinol Metab 2000; 85: 2664-2669
J, Peterson RE, Gautier T, Sturla E. Male pseudohermaphroditism secondary to 5 alpha-reductase deficiency - a model for the
role of androgens in both the development of the male phenotype and the evolution of a male gender identity. J Steroid Biochem
43. Wilson JD, Griffin
JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993;14:577-593
44. Reiner WG, Gearhart
JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med
HF. Gender identity outcome in femaleraised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile
ablation. Arch Sex Behav 2005; 34:423-438
46. Swaab DF, Hofman
MA. Sexual differentiation of the human brain. A historical perspective. Prog Brain Res 1984;61: 361-374
47. Goldstein JM,
Seidman LJ, Horton NJ et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging.
Cereb Cortex 2001;11:490- 497
L, Gonzalez-Soriano J, Rodriguez JR, DeFelipe J. Gender differences in human cortical synaptic density. Proc Natl Acad Sci
U S A 2008;105:14615-4619
49. Amunts K, Schleicher
A, Borgel U, Mohlberg H, Uylings HB, Zilles K. Broca's region revisited: cytoarchitecture and intersubject variability. J
Comp Neurol 1999;412:319-41
50. Amunts K, Schleicher
A, Zilles K. Cytoarchitecture of the cerebral cortex-more than localization. Neuroimage 2007;37:1061-1065
51. Allen JS, Damasio
H, Grabowski TJ, Bruss J, Zhang W. Sexual dimorphism and asymmetries in the gray-white composition of the human cerebrum.
Neuroimage 2003; 18:880-894
52. Savic I. Brain
imaging studies of the functional organization of human olfaction. Chem Senses 2005;30:222-223
53. Savic I, Lindstrom
P. PET and MRI show differences in cerebral asymmetry and functional connectivity between homoand heterosexual subjects. Proc
Natl Acad Sci U S A 2008;105:9403-9408
54. LeVay S. A difference
in hypothalamic structure between heterosexual and homosexual men. Science 1991;253: 1034-1037
55. Allen LS, Gorski
RA. Sexual orientation and the size of the anterior commissure in the human brain. Proc Natl Acad Sci U S A 1992;89:7199-7202
56. Hines M. Sex
steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children. Ann N Y Acad Sci 2003;1007:272-282
57. Savic I, Engel
J Jr. Sex differences in patients with mesial temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 1998;65:910-912
58. Swaab DF. The
human hypothalamus. Basic and clinical aspects. Part I: Nuclei of the hypothalamus. In: Aminoff MJ, Boller F, Swaab DF eds
Handbook of Clinical Neurology. Amsterdam; Elsevier 2003:127-140
59. Bao AM, Swaab
DF. Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic
paraventricular nucleus and the role of sex hormones. Neuroendocrinology 2007;85:27-36
60. Brockhaus H.
Beitrag zur normalen Anatomie des Hypothalamus und der Zona incerta beim Menschen. J Psychol Neurol 1942;51:96-196
61. Braak H, Braak
E. The hypothalamus of the human adult: chiasmatic region. Anat Embryol (Berl) 1987;175:315-330
62. Koutcherov Y,
Paxinos G, Mai JK. Organization of the human medial preoptic nucleus. J Comp Neurol 2007;503: 392-406
63. Swaab DF, Fliers
E. A sexually dimorphic nucleus in the human brain. Science 1985;228:1112-1115
64. Allen LS, Hines
M, Shryne JE, Gorski RA. Two sexually dimorphic cell groups in the human brain. J Neurosci 1989; 9:497-506
65. Swaab DF, Hofman
MA. Sexual differentiation of the human hypothalamus: ontogeny of the sexually dimorphic nucleus of the preoptic area. Brain
Res Dev Brain Res 1988;44:314-318
66. Hofman MA, Swaab
DF. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat 1989;164:55-72
67. Swaab DF, Gooren
LJ, Hofman MA. The human hypothalamus in relation to gender and sexual orientation. Prog Brain Res 1992;93:205-219
A, Swaab DF. A sex difference in the hypothamaic uncinate nucleus: relationship to gender identity. Brain 2008;131:3132-3146
69. Byne W, Lasco
MS, Kemether E et al. The interstitial nuclei of the human anterior hypothalamus: an investigation of sexual variation in
volume and cell size, number and density. Brain Res 2000;856:254-258
70. Byne W, Tobet
S, Mattiace LA et al. The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex,
sexual orientation, and HIV status. Horm Behav 2001;40:86-92
71. Schober JM,
Pfaff D. The neurophysiology of sexual arousal. Best Pract Res Clin Endocrinol Metab 2007;21: 445-461
72. Allen LS, Gorski
RA. Sexual dimorphism of the anterior commissure and massa intermedia of the human brain. J Comp Neurol 1991;312:97-104
A, Kruijver FP, Fodor M, Swaab DF. Sex differences in the distribution of androgen receptors in the human hypothalamus. J
Comp Neurol 2000;425:422-435
74. MacLean PD,
Ploog DW. Cerebral representation of penile erection. J Neurophysiol 1962;25:29-55
75. Ishunina TA,
Fischer DF, Swaab DF. Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer's disease.
Neurobiol Aging 2007;28:1670-1681
76. Kruijver FP,
Balesar R, Espila AM, Unmehopa UA, Swaab DF. Estrogen receptor-alpha distribution in the human hypothalamus in relation to
sex and endocrine status. J Comp Neurol 2002;454:115-139
77. Kruijver FP,
Balesar R, Espila AM, Unmehopa UA, Swaab DF. Estrogen-receptor-beta distribution in the human hypothalamus: similarities and
differences with ER alpha distribution. J Comp Neurol 2003;466:251-277
78. Coolidge FL,
Thede LL, Young SE. The heritability of gender identity disorder in a child and adolescent twin sample. Behav Genet 2002;32:251-257
79. Hare L, Bernard
P, Sanchez FJ et al. Androgen receptor repeat length polymorphism associated with male-to-female transsexualism. Biol Psychiatry
M, van Trotsenburg M, Repa C, Marton E, Huber JC, Bernaschek G. Sex chromosome aberrations and transsexualism. Fertil Steril
S, Westberg L, Nilsson S et al. Sex steroid-related genes and male-to-female transsexualism. Psychoneuroendocrinology 2005;30:657-664
82. Bentz EK, Hefler
LA, Kaufmann U, Huber JC, Kolbus A, Tempfer CB. A polymorphism of the CYP17 gene related to sex steroid metabolism is associated
with female-to-male but not male-to-female transsexualism. Fertil Steril 2008; 90:56-59
V, Manikkam M, Recabarren S, Foster D. Prenatal testosterone excess programs reproductive and metabolic dysfunction in the
female. Mol Cell Endocrinol 2005;246:165-174
84. Mueller A, Gooren
LJ, Naton-Schotz S, Cupisti S, Beckmann MW, Dittrich R. Prevalence of polycystic ovary syndrome and hyperandrogenemia in female-to-male
transsexuals. J Clin Endocrinol Metab 2008;93:1408-1411
85. Zucker KJ, Bradley
SJ, Oliver G, Blake J, Fleming S, Hood J. Psychosexual development of women with congenital adrenal hyperplasia. Horm Behav
86. Dessens AB,
Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex
87. Dessens AB,
Cohen-Kettenis PT, Mellenbergh GJ, vd Poll N, Koppe JG, Boer K. Prenatal exposure to anticonvulsants and psychosexual development.
Arch Sex Behav 1999;28: 31-44
88. Gender Identity
Research and Education Society, information page:http://www.gires.org.uk/genderdev.php
89. DES sons' International
PT, van Goozen SH, Doorn CD, Gooren LJ. Cognitive ability and cerebral lateralisation in transsexuals. Psychoneuroendocrinology
PT, Gooren LJ. Transsexualism: a review of etiology, diagnosis and treatment. J Psychosom Res 1999; 46:315-333.
PT, Delemarre-van de Waal HA, Gooren LJ. The treatment of adolescent transsexuals: changing insights. J Sex Med 2008;5:1892-1897
93. Wallien MS,
Cohen-Kettenis PT. Psychosexual outcome of gender-dysphoric children. J Am Acad Child Adolesc Psychiatry 2008;47:1413-1423
94. Zhou JN, Hofman
MA, Gooren LJ, Swaab DF. A sex difference in the human brain and its relation to transsexuality. Nature 1995;378:68-70
95. Kruijver FP,
Zhou JN, Pool CW, Hofman MA, Gooren LJ, Swaab DF. Male-to-female transsexuals have female neuron numbers in a limbic nucleus.
J Clin Endocrinol Metab 2000;85:2034-2041
96. Chung WC, De
Vries GJ, Swaab DF. Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood.
J Neurosci 2002;22:1027-1033
97. Berglund H,
Lindstrom P, Dhejne-Helmy C, Savic I. Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling
odorous steroids. Cereb Cortex 2008;18:1900-1908
98. Gizewski ER,
Krause E, Schlamann M et al. Specific cerebral activation due to visual erotic stimuli in male-to female transsexuals compared
with male and female controls: an fMRI study. J Sex Med 2009;6:440-448
F. Swaab, M.D., Ph.D.
Institute for Neuroscience, Amsterdam. (*)
author: Dick F. Swaab
for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam ZO, The Netherlands
(*) The Netherlands
Institute for Neuroscience is an institute of the Royal Netherlands Academy of Arts and Sciences.
Back to Harry Benjamin Syndrome International Homepage