Review

The Neuroscientist

Sex Differences in the Brain, Behavior, 16(5) 550­–565

© The Author(s) 2010
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DOI: 10.1177/1073858410377005
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Ai-Min Bao1 and Dick F. Swaab2

Abstract
Sex differences in the brain are reflected in behavior and in the risk for neuropsychiatric disorders. The fetal brain
develops in the male direction due to a direct effect of testosterone on the developing neurons, or in the female
direction due to the absence of such a testosterone surge. Because sexual differentiation of the genitals takes place earlier
in intrauterine life than sexual differentiation of the brain, these two processes can be influenced independently of each
other. Gender identity (the conviction of belonging to the male or female gender), sexual orientation (heterosexuality,
homosexuality, or bisexuality), pedophilia, sex differences in cognition, and the risks for neuropsychiatric disorders are
programmed into our brains during early development. There is no proof that postnatal social environment has any
crucial effect on gender identity or sexual orientation. Structural and functional sex differences in brain areas, together
with changes in sex hormone levels and their receptors in development and adulthood, are closely related to sex
differences in behavior and neuropsychiatric disorders. Knowing that such a relationship exists may help bring about
sex-specific therapeutic strategies.

Keywords
sex difference, gender identity, sexual orientation, stress, depression

Sex differences in the brain are reflected in behavior from
birth onward. For example, female neonates look more at
human faces on their first day of life whereas male infants
look more at mechanical mobiles (Connelan and others
2000). In childhood, girls prefer to play with dolls while
boys prefer toy cars and balls, which is already obvious at
3 to 8 months of age (Alexander and others 2009). Such
toy preferences cannot be explained by an effect of social
pressure, because when dolls, toy cars, and balls were
offered to green vervet monkeys, the females consistently
chose the dolls and showed anogenital sniffing, whereas
the males were more interested in playing with the toy
cars and balls (Alexander and Hines 2002; Fig. 1). Tes-
tosterone levels during pregnancy seem to play a role in
the development of such sex differences in behavior,
because girls who were exposed to high testosterone lev-
els in the womb, as in cases of congenital adrenal hyperpla-
sia (CAH), tended to choose boys as playmates, preferred
boys’ toys, and exhibited some male-typical personality
features (Mathews and others 2009; Nordenstrom and
others 2002). The sex differences in playing behavior
thus seem to have originated early on in our evolution,
before the hominids, and are imprinted during our intra-
uterine development under the influence of testosterone.
A similar sex difference is seen in spontaneous drawings
of children. A Japanese study showed that 5- to 6-year-
old girls tend to draw human figures, flowers, and butter-
flies in bright colors, but boys prefer to draw more technical
objects, weapons and fighting, and means of transporta-
tion, in bird’s-eye view compositions and in darker colors
(Fig. 2). Girls with CAH showed male drawing charac-
teristics, even if the CAH were treated immediately after
birth (Iijima and others 2001; Fig. 3). Apparently, fetal
exposure to higher levels of male hormones has lasting
effects on behavior and artistic expression. It should be
noted that a child’s atypical toy preference does not nec-
essarily predict a gender identity disorder in adulthood
(see below and Wallien and Cohen-Kettenis 2008).
Sex differences are found in adult behaviors as well.
For instance, aggressive behavior in men has also been
1
Department of Neurobiology, Institute of Neuroscience, Zhejiang
University School of Medicine, Hangzhou, China
2
Netherlands Institute for Neuroscience, an Institute of the Royal
Netherlands Academy of Arts and Sciences, Amsterdam, The
Netherlands
Corresponding Author:
Prof. Dr. Ai-Min Bao, Department of Neurobiology, Institute
of Neuroscience, Zhejiang University School of Medicine,
Hangzhou, China
Email: baoaimin@zju.edu.cn

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Bao and Swaab 551

Figure 1. Examples of a female and a male animal touching/reacting to toys. The female animal (left) appears to be conducting an
anogenital inspection of the toy doll, similar to inspections of infant vervet monkeys. The male animal (right) appears to be moving
the car along the ground in a manner similar to that which a child might use. Reprinted from Alexander and Hines, Copyright 2002,
with permission from Elsevier.

related to prenatal testosterone levels (Mazur and Booth
1998). More importantly, sex differences are also reflected
in the risk of contracting neuropsychiatric disorders such
as Alzheimer’s disease (AD), schizophrenia, drug abuse,
depression, and anxiety (Table 1).
Development of Sex Differences
in the Brain
Organizational and Activational Effects
of Sex Hormones
The fetal testicles and ovaries develop under the influence
of a cascade of genes, starting with the sex-determining
gene on the Y chromosome (sex-determining region Y,
SRY). Testosterone and its conversion into dihydrotestos-
terone between weeks 6 and 12 of pregnancy are essential
for the formation of a boy’s penis, prostate, and scrotum,
whereas the development of the female sexual organs in
the womb is based primarily on the absence of androgens.
Once the differentiation of these sexual organs is settled,
sexual differentiation of the brain happens, mainly under
the organizing effects on the brain of sex hormones that
are permanent (Swaab 2004). Later, during puberty, the
brain circuits that were organized from the womb will
be activated by sex hormones. The genes SRY and ZFY
(gene that encodes zinc finger Y-chromosomal protein)
are candidates for this action inasmuch as they are expressed
until very advanced ages in the human brain, despite that,
strictly speaking, the role of these genes in sexual differ-
entiation stops during development (Bocklandt and Vilain
2007; Swaab 2004). In addition, it has been found that
50 genes are expressed at different levels in the brains of
male and female mouse fetuses, even before the sex hor-
mones come into play (Dewing and others 2003). There-
fore, sexual differentiation of the brain may not be caused
by hormones alone, although they are very important for
gender identity and sexual orientation.
There are two critical periods in human development
when testosterone levels are known to be higher in boys:

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552 The Neuroscientist 16(5)

Figure 2. Left, A, Picture drawn by a 5-year-old girl. B, Picture drawn by a 6-year-old girl. C, Picture drawn by a 5-year-old boy. Right,
A, Bird’s-eye view of an intersection drawn by a 6-year-old boy. B, Trains are drawn in a pile by a 5-year-old boy. Reprinted from
Iijima and others, Copyright 2001, with permission from Elsevier.

the first period occurs in midpregnancy; the second takes
place in the first three months after birth. These fetal and
neonatal risings of testosterone, together with the func-
tional steroid receptor activity, are thought to fix, to a
major degree, the development of structures and circuits
in the brain for the rest of a boy’s life, and are called “pro-
gramming” or “organizing” effects. The “activating” effects
of rising hormone levels during puberty stimulates cir-
cuits and behavioral patterns that have been set up during
development, in a masculinized and defeminized direc-
tion for male brains, or in a feminized and demasculin-
ized direction for female brains (Swaab 2004).
As sexual 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
(that starts in the second half of pregnancy and becomes
overt upon reaching adulthood), these two processes may
be influenced independently. In rare cases, this may result
in transsexuality, that is, people with male sexual organs
who nevertheless experience their identity as female, or
vice versa. It also means that in the event of an ambigu-
ous sex at birth, the degree of masculinization of the geni-
tals may not always reflect the degree of masculinization
of the brain (Swaab 2004). Structural differences in the
brain resulting from the interaction among genes, sex
hormones, and developing brain cells are thought to be the
basis of sex differences in a wide spectrum of behaviors,
including gender role (behaving as a man or a woman in
society), gender identity (the conviction of belonging to
the male or female gender), and sexual orientation (het-
erosexuality, homosexuality, or bisexuality). Factors that
interfere with the interactions between sex hormones and
the developing brain systems in the womb may perma-
nently influence not only later behavior, but may also
carry the risk of neuropsychiatric disorders.
Sex Differences in Brain Disorders
Sex differences in the brain and hormone levels are the
functional basis of the often pronounced sex differences
in the prevalence of neuropsychiatric disorders. The
proportions of cases range from more than 75% women
in Rett syndrome, lymphocytic hypophysitis, anorexia
and bulimia nervosa, and hypnic headache syndrome,
to more than 75% men in dyslexia, attention-deficit
hyperactivity disorder, autism, sleep apnea, Gilles de la

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Bao and Swaab 553
Figure 3. A, A car drawn by a 5-year-old girl with congenital
adrenal hyperplasia (CAH). B, Bird’s-eye view picture drawn by
a 7-year-old girl with CAH. Reprinted from Iijima and others,
Copyright 2001, with permission from Elsevier.
Tourette syndrome, Kallmann syndrome, and Kleine-
Levin syndrome (for references, see Swaab 2003; Table 1).
Sex differences are not only shown in the prevalence but
also in the signs, symptoms, and course of the disorders.
Not only do men suffer from schizophrenia 2.7 times
more often than women, they are also prone to a more
severe form, a poorer premorbid functioning experience,
earlier onset, more negative symptoms and cognitive
defects, and exhibit a greater number of structural brain
abnormalities, such as a more severe enlargement of the
lateral ventricles. In addition, male patients tend to have
more severe relapses and to respond to neuroleptic medi-
cation less favorably. Female patients, on the other hand,
display more affective symptoms, auditory ­hallucinations,
and persecutory delusions. Moreover, an interaction with
gender was observed in the second trimester of pregnancy
when prenatal ­expo­sure to maternal stress was studied as
a risk factor for schizophrenia, with male fetuses having
a higher risk ratio (Swaab 2003). Factors that produce
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Table 1. Ratios for Women over Men Suffering from a
Selection of Neurological and Psychiatric Diseases
Disease Women : Men (%)
Rett syndrome 100 : 0
Postoperative hyponatremic 96 : 4
encephalopathy with permanent
damage or death
Anorexia nervosa 93 : 7
Lymphocytic hypophysitis 90 : 10
True (central) precocious puberty 90 : 10
Hypnic headache syndrome 84 : 16
Bulimia 75 : 25
Senile dementia of the Alzheimer type 74 : 26
Multiple sclerosis 67 : 33
Anxiety disorder 67 : 33
Anencephaly 67 : 33
Posttraumatic stress disorders 70 : 30
Dementia 64 : 36
Unipolar depression, dysthymia 63 : 37
Whiplash 60 : 40
Severe learning disability 38 : 62
Substance abuse 34 : 66
Amyotropic lateral sclerosis 33 : 67
Stuttering 29 : 71
Schizophrenia 27 : 73
REM sleep behavioral disorder 24 : 76
Male-to-female vs. female-to-male 28 : 72
transsexuals
Dyslexia 23 : 77
ADHD 20 : 80
Autism 20 : 80
Sleep apnea 18 : 82
Kallmann syndrome 17 : 83
REM sleep disorder 13 : 87
Gilles de la Tourette syndrome 10 : 90
Kleine-Levin syndrome 0 :100
Abbreviations: REM = rapid eye movement; ADHD = attention-deficit
hyperactivity disorder. (For references, see Swaab 2003.)
normal sexual dimorphism in the brain, particularly in the
cortex, may be associated with modulating insults produc-
ing schizophrenia (Goldstein and others 2002).
Other examples of sex differences in neurological dis-
eases are those following restricted left-­hemisphere lesions,
resulting in aphasia in 41% of the men and 11% of the
women, and manual apraxia in 6% of the women and
42% of the men. After severe subarachnoid hemorrhage,
mortality in women was lower (37%) than in men (53%),
whereas the incidence of a favorable outcome was higher
in women (42%) than in men (26%). Female traumatic
brain-injury patients also had a better predicted outcome
than male patients (for references, see Swaab 2003).
According to some studies, the prevalence of AD is
higher in women than in men (Letenneur and others 2000),
although some other researchers did not find such an
554 The Neuroscientist 16(5)

association between AD and gender and suggested that

the excess number of female AD is due to the longer life
expectancy of women (Hebert and others 2001). How-
ever, the observation of an increased number of nucleus
basalis of Meynert neurons containing more AD pathology
in women compared with age-matched men (Salehi and
others 2000) and the association found between AD and a
locus on the X-chromosome (Zubenko and others 1998)
supports the presence of sex differences in AD. Lower
endogenous estradiol levels are correlated with poor cog-
nitive, behavioral, and functional status in older but non-
demented women, whereas higher free testosterone levels
are associated with better scores on visual and verbal
memory, visuospatial functioning, and visuomotor scan-
ning in elderly nondemented men. Several studies have
reinforced the idea that the postmenopausal decrease in
estrogen levels may be an important factor in triggering
the pathogenesis of AD, inasmuch as women with high
serum concentrations of bioavailable estradiol are less
likely to develop cognitive impairment than women with
low concentrations. In older men, endogenous testosterone
levels are not associated with risk for cognitive decline
and AD, whereas higher estrogen levels increase such a
risk. Cerebrospinal fluid levels of estradiol were found to
be lower in female AD patients than in controls, and within
the female AD group the estradiol levels are inversely
correlated with Ab-42 concentrations, which has been
interpreted as corresponding to the beneficial effects of
estrogens on AD (for references, see Bao and others 2008).
Whether sex differences in the brain that arise in deve­
Figure 4. Thionin-stained frontal section (6 mm) of the
lopment (organizing effects) are indeed the basis for the hypothalamus of (A) a 28-year-old man and (B) a 10-year-
sex differences in neurological or psychiatric diseases still old girl. Arrows show the extent of the sexually dimorphic
has to be established. Alternative mechanisms involved nucleus of the preoptic area (SDN-POA). Note the large
may be the immediate effects of differences in circulating blood vessel penetrating the SDN-POA and note that the male
sex hormone levels (activating effects), caused by sex SDN is larger than that of the female. Bar represents 1 mm.
hormone-stimulated gene transcription, as shown, for (Unpublished figure from the study of Swaab and Fliers 1985.)
example, in depression (see below).

sex difference in the sexually dimorphic nucleus of the

Sex Differences in the Human Brain
in Relation to Gender Identity, Sexual
Orientation, and Pedophilia
Sex difference in brain weight in allometric relation to
body length is already present from the age of 2 years
(Swaab and Hofman 1984). Sex differences in adult brain
structures have been observed from macroscopic to ultra-
microscopic levels (Swaab 2003). In addition, a large
number of functional sex differences in different brain
regions have been described (Swaab and Garcia-Falgueras
2009). The present review will mention just a few of the
now countless human brain sex differences. It started in the
hypothalamus, where our group first found a structural
preoptic area (SDN-POA), which was later also called
the interstitial nucleus of the anterior hypothalamus-1
(INAH1), or the intermediate nucleus (InM) of the human
hypothalamus. The SDN-POA was found to be 2.5 times
larger and to contain 2.2 times more cells in men than in
women (Swaab and Fliers 1985; Fig. 4). These sex differ-
ences develop only after 5 years of age and disappear
temporarily after the age of 50 years (Hofman and Swaab
1989; Fig. 5). In addition, Allen and others described two
other cell groups, INAH-2 and INAH-3, which showed
larger volumes in men compared to women (2.8 and 2
times greater, respectively). Moreover, sex differences
were found in volume and neuron number both in the
central nucleus of the human bed nucleus of the stria

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Bao and Swaab 555
Figure 5. Age-related changes in the total cell number of
the sexually dimorphic nucleus of the preoptic area (SDN-
POA) in human hypothalamus. The general trend in the data
is enhanced by using smoothed growth curves. Note that in
males SDN cell number steeply declines between the ages of
50 and 70 years, whereas in females a more gradual cell loss is
observed around the age of 80 years. These curves demonstrate
that the reduction in cell number in the human SDN in the
course of aging is a nonlinear, sex-dependent process. Reprinted
from Hofman and Swaab 1989, with permission.
terminalis (BSTc; Zhou and others 1995; Fig. 6) and in
the INAH3, but not in the INAH4 (Garcia-Falgueras and
Swaab 2008; Fig. 7). Other structural sex differences have
been found, for example, in the subcortical human ante-
rior commissure, the interthalamic adhesion, the corpora
mamillaria (for references, see Swaab 2003), and the cor-
tex (Goldstein and others 2001).
Irreversible programmed gender identity. In the 1960s and
1970s it was thought that a child was born as a “tabula
rasa” and was subsequently forced into the male or female
direction by the convention of society. J. Money who held
such an idea also believed that gender imprinting does not
start until the age of 1 year (Money and Erhardt 1972).
Such a view had devastating results in the case of David
Reimer, in which an 8-month-old boy, who lost his penis
due to a mistake during minor surgery (for correcting a
phimosis), was made into a girl, based upon Money’s
opinion. The child’s testicles were removed before the
age of 17 months. In addition, he was dressed in girl’s
clothes, received psychological counseling, and was given
estrogens in puberty (Colapinto 2000). According to
Money, this child developed as a normal female. How-
ever, it later became clear that this had not been the case
at all. Reimer never identified as female, and he began to
live again as a male at age 14 years (Diamond and Sig-
mundson 1997). Unfortunately, because of years of severe
depression, financial instability, and a dissolving mar-
riage, Reimer committed suicide in 2004. This story
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illustrates the strength of the irreversible programming
influence on gender identity during the intrauterine
period. Other cases concerning the results of enzymatic
disorders or of cloacal exstrophy also support the idea
that the early permanent programming of gender identity
in the brain is deter­mined by biological factors such as
intrauterine androgen exposure, rather than by social
environment and learning (Swaab 2004).
Transsexuality and the brain. Transsexuality is the most
extreme gender-identity disorder consisting of the unshak-
able conviction of belonging to the opposite gender. There
are no indications that postnatal social factors could be
responsible for this disorder. On the other hand, only 23%
of childhood gender problem cases will lead to transsexu-
ality in adulthood (Coolidge and others 2002). A number
of factors have been found to be a risk for transsexuality
(Table 2) including chromosomal abnormalities, poly-
morphisms of the genes for the estrogen receptor (ER) a,
ERb, androgen receptor (AR), and aromatase or cyto-
chrome P450 (CYP)-17 (for references, see Swaab and
Garcia-Falgueras 2009). Abnormal hormone levels dur-
ing early development may also play a role, because girls
with CAH have an increased chance of becoming trans-
sexual. It should be noted that although the likelihood of
transsexuality developing in CAH cases is 100 to 300
times higher than normal (in population, 1:10,000 to
1:30,000), the risk for transsexuality in CAH is still only
1% to 3%, whereas the probability of serious gender
problems in this group is 5.2%. The consensus is, there-
fore, that girls with CAH should be raised as girls, even
if their genitals are masculinized. Epileptic women who
were given phenobarbital or diphantoin during preg-
nancy also have an increased risk of giving birth to a
transsexual child (Dessens and others 1999), because
both of the chemicals may change the metabolism of the
sex hormones and can act on the sexual differentiation
of the child’s brain. Moreover, homosexual male-to-
female (MtF) transsexuality is more likely to occur in
men with a large number of older brothers (Gomez-Gil
and others 2010).
The theory of the origin of transsexuality is based on
the fact that the differentiation of sexual organs appears
before the sexual differentiation of the brain. As the two
processes have different schedules, it is theoretically pos-
sible that they take different routes under the influence of
differently timed factors. If this is the case, one might
expect to find, in transsexuals, female sexual organs with
a male brain, and vice versa. Indeed such reversals have
been found in the BSTc and in the INAH3, two brain
structures that are also involved in sexual behavior in
rodents.
In men, the BSTc volume was twice as large as in
women and contained twice as many somatostatin neurons
556 The Neuroscientist 16(5)

Figure 6. Left, Representative sections of the central nucleus of the bed nucleus of the stria terminalis (BSTc) innervated by
vasoactive intestinal polypeptide (VIP). A, Heterosexual man; B, heterosexual woman; C, homosexual man; D, male-to-female
transsexual. Scale bar = 0.5 mm. LV = lateral ventricle. Note the two parts of the BST in A and B: small medial subdivision (BSTm)
and large oval-sized central subdivision (BSTc). Note also the sex difference (A vs. B) and the fact that the male-to-female
transsexual (D) has a female BSTc in size and type of innervation. Reprinted by permission from Macmillan Publishers Ltd:   Nature,
Zhou and others, copyright 1995. Right, 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. The sex hormone disorder patients S1, 2 , 3 , 5 , 6, 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) also becomes 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 female-to-male transsexual
(FMT) is fully in the male range. 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 (25 years of age) = Turner syndrome (45, X0; ovarian hypoplasia). M2 (73 years of age) =
postmenopausal status. Reprinted from Kruijver and others with permission, Copyright 2000, The Endocrine Society.

(Kruijver and others 2000; Zhou and others 1995; Fig. 6).
The same was true for the INAH3, which was found to be
1.9 times larger in men than in women and contained 2.3
times more neurons (Garcia-Falgueras and Swaab 2008;
Fig. 7). In addition, a female BSTc and INAH3 have been
found in MtF transsexuals (Figs. 6, 7). Moreover, in the
only female-to-male (FtM) transsexual, the BSTc and
INAH3 had all the male characteristics (Garcia-Falgueras
and Swaab 2008; Kruijver and others 2000; Zhou and
others 1995). Furthermore, a functional imaging study
also found that MtF transsexuals had sex-atypical hypo-
thalamus activation by putative pheromones (Berglund
and others 2008). These observations thus support the
neurobiological theory about the origin of transsexuality,
that is, it is the sizes, the neuron numbers, the functions
and connectivity of brain structures, but not the sex of the
sexual organs, birth certificates, or passports, that matches
these people’s gender identities.
Unfortunately, the sex difference in the BSTc volume
does not become apparent until early adulthood (Chung
and others 2002), which means that this nucleus cannot
be used for early diagnosis of transsexualism.
Sexual orientation and the brain. Sexual orientation
refers to the gender (male or female) to which a person is
attracted, that is, to the opposite sex (heterosexual), to the
same sex (homosexual), or to both sexes (bisexual). Sex-
ual orientation is also determined during early develop-
ment, under the influence of genetic background and factors
that influence the interactions between sex hormones and
the developing brain and awakens during puberty under the
influence of sex hormones. The apparent impossibility of
changing a person’s sexual orientation (LeVay 1991) is a

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Bao and Swaab 557

Figure 7. A, The interstitial nucleus of the anterior hypothalamus (INAH)-3 volume in thionin staining in different groups,
according to their gender identity and hormonal changes in adulthood. M = control male group; F = control female group; MtF =
male-to-female transsexual group; CAS = castrated male group; PreM = premenopausal women; PostM = postmenopausal women.
Bars represent means and standard errors of the mean (SEM). MtF and F groups were statistically different compared to the M
group (P < 0.018 and P < 0.013, respectively). Hormonal changes in adulthood (CAS vs. M and PreM vs. PostM groups) showed
no difference in INAH3 volume. Note that the volume of the female-to-male transsexual subject (FtM, in the male group, 51
years old) is in the male range. A gender dysphoric male-to-female patient who was not treated in any way (S7, in the MtF group,
84 years old) showed a male value for INAH3 volume. B, Distribution of the INAH3 number of neurons among different groups.
Statistically differences were found among men (M) and women (F) (P < 0.029) and among men (M) and MtF transsexual groups
(P < 0.002). An FtM transsexual person (51 years old) had a masculine INAH3 number of neurons, whereas the gender dysphoric
nontreated patient (S7, in the MtF group, 84 years old) had a similar number of neurons to the other transsexuals examined.
Reprinted from Garcia-Falgueras and Swaab 2008, with permission from Oxford University Press.

major argument against the role of society or environment
in the emergence of homosexuality, as well as against the
idea that homosexuality is a lifestyle choice.
Family and twin studies have indicated a genetic
component of over 50% in the development of sexual
orientation, but it is unclear which genes exactly play
such a role. A number of genetic studies have suggested
a maternal transmission, that is, an X-linked inheritance.
The X-chromosome has accumulated genes involved in
sex, reproduction, and cognition. Xq28 was found to be
a potential genetic marker linked to male homosexuality
(Hamer and others 1993); however, 18 years after the
initial findings, the exact genes involved have not yet been
identified. A different technique also indicated that women
with gay sons had an extreme skewing of X-inactivation
compared with mothers without gay sons. Although this
unusual methylation pattern supports a possible role of
the X-chromosome in male homosexuality, its mechanism
of action is far from clear (Bocklandt and others 2006).
Given the complexity of the development of sexual
orientation, it is likely to involve many genes. A genome-
wide linkage screening indeed identified several chromo-
somal regions and candidate genes for further exploration
(Mustanski and others 2005).
Several additional factors during development influ-
ence our sexual orientation (Table 3). The large propor-
tion of bisexual or homosexual girls with CAH indicates
a role of abnormal sex hormone levels in development.
The prescription medicine diethylstilbestrol (DES), an
estrogen-like substance that aimed to prevent miscar-
riage, has turned out, however, not only to give a slightly
elevated risk of cervical cancer but also increased the
chance of bisexuality or homosexuality in girls. The fra-
ternal birth order effect indicating that the chance a boy
will be homosexual increases with the number of his
older brothers is putatively explained by the progressive
immunization of some mothers to Y-linked minor histo-
compatibility antigens with each successive male fetus.
Moreover, prenatal exposure to nicotine, amphetamine,
or thyroid hormones increases the chances of giving birth

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558 The Neuroscientist 16(5)
Table2. Prenatal Factors that Influence Gender Identity that
May Result in Transsexuality
Genetic Factors
• Apparent from twin studies
• Rare chromosomal disorders
• Polymorphisms in ERb, androgen receptor, and aromatase
genes
Hormones
• Phenobarbital/diphantoin taken by pregnant mother
• Cloacal exstrophy
• 5a-Reductase-2 or 17b-hydroxy-steroid-dehydrogenase-3
deficiency
• Girls with CAH
• Complete androgen insensitivity syndrome results in XY
heterosexual females with feminine identity
• DES sons: 25% gender problems (needs formal study and
confirmation)
Immune Response?
• Homosexual male-to-female transsexuality is more likely to
occur in men with a large number of older brothers
Social Factors?
• Postnatally no evidence
Note: Abbreviations: CAH = congenital adrenal hyperplasia; DES =
diethylstilbestrol. (For references, see Gomez-Gil and others 2010;
Swaab and Garcia-Falgueras 2009.)
to lesbian daughters. Furthermore, a stressed pregnant
woman has a greater chance of giving birth to a homo-
sexual son. Contrarily, solid proof is lacking for postnatal
development playing an important role in directing sex-
ual orientation. Children born after artificial insemination
with donor sperm and raised by lesbian couples were het-
erosexually oriented (for references, see Swaab and Garcia-
Falgueras 2009). Proof for the idea that homosexuality is
the result of upbringing, or that it is a lifestyle choice or
an effect of social learning is also lacking (LeVay 1991).
Therefore, it is totally irrational that some people still for-
bid their children to play with homosexual friends mainly
for fear that homosexuality is contagious or can be learned.
Several structural and functional differences in the
brain have been described in relation to sexual orienta-
tion. The first difference was found by Swaab’s group in
the suprachiasmatic nucleus (SCN), the biological clock,
which turned out to be twice as large in homosexual as in
heterosexual men (Swaab 2008). In 1991, LeVay reported
that homosexual men have a smaller volume of INAH-3
(LeVay 1991). Allen and Gorski found that, compared
with heterosexual men, homosexual men have a larger
anterior commissure, a structure that is usually larger in
women than in men, which takes care of the left-right
temporal cortex connection and may thus be involved in
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Table 3. Prenatal Factors that May Influence Sexual
Orientation
Genetic Factors
• Apparent from twin studies
• Apparent from molecular genetics
Hormones
• Girls with CAH
• DES
Chemical Factors
• Prenatal exposure to nicotine, amphetamines, or thyroid
medication
Immune Response
• Homosexual orientation in men is more likely to occur in
men with a large number of older brothers
Social Factors?
• Stress in the mother during pregnancy
• Being raised by transsexual or homosexual parents does
not affect sexual orientation
Note: Abbreviations: CAH = congenital adrenal hyperplasia;
DES = diethylstilbestrol. (For references, see Swaab and
Garcia-Falgueras 2009.)
sex differences in cognitive abilities and language (Allen
and Gorski 1992). Savic and Lindström have found that
the difference in anterior commissure size may possibly
be related to the sex-atypical hemispheric asymmetries
observed in homosexual men and women (Savic and
Lindstrom 2008; Swaab 2008). No difference was found
in the size or number of neurons in the BSTc in relation to
sexual orientation (Fig. 6).
Functional scanning also revealed brain differences in
relation to sexual orientation: The hypothalamus of homo­
sexual men was not as responsive to fluoxetine as that of
heterosexual men, indicating different activities of the
serotoninergic system (Kinnunen and others 2004). Uncon­
scious personal communication through pheromones is a
well-known phenomenon. Savic and Lindstrom probed
the influence of pheromones on sexual behavior using
position-emission tomography (PET) and pheromones
that are excreted in perspiration in concentrations that are
10 times higher in men than in women. They found that
such pheromones stimulated the hypothalamus of hetero-
sexual women and homosexual men in the same way, but
heterosexual men were not stimulated by such a male
scent, which suggests that pheromones may contribute to
the way that we determine our partner-choice (Savic and
Lindstrom 2008). In a follow-up study, they found that les-
bian women, as compared with heterosexual women, rea­
cted to pheromones in a sex-atypical, almost reciprocal,
Bao and Swaab 559

Figure 8. Covariations with the respective amygdala seed region in heterosexual and homosexual subjects. The Sokoloff scale
indicates T values. Clusters detected at T = 3.0 are superimposed on the standard magnetic resonance image of the brain. In
homosexual men (HoM), like in heterosexual women (HeW), the connections were more widespread from the left amygdala, in
homosexual women (HoW) and heterosexual men (HeM), on the other hand, from the right amygdala. Furthermore, in HoM and
HeW the connections were primarily displayed with the contralateral amygdala and the anterior cingulate, in HeM and HoW with
the caudate, putamen, and the prefrontal cortex. Reprinted with permission from Savic and Lindstrom, Copyright 2008 National
Academy of Sciences, U.S.A.

way. This group, using, respectively, magnetic resonance
volumetry and PET measurements, also found sex-atypical
cerebral asymmetry and functional connections in homo-
sexual subjects that cannot be primarily ascribed to learned
effects but suggest a linkage to neurobiological entities
(Savic and Lindstrom 2008; Swaab 2008; Fig. 8).
Pedophilia and the brain. Because it is a taboo topic,
little is known about the risk factors for pedophilia that
concern sexual orientation toward prepubertal children.
The familial transmission of pedophilia indicates genetic
involvement (Gaffney and others 1984). Compared with
homosexual and heterosexual control subjects, pedophiles
showed decreased gray matter volumes in the ventral
striatum, extending into the nucleus accumbens, the orbi-
tofrontal cortex, and the cerebellum (Schiffer and others
2007). In addition, smaller volumes of hypothalamus,
amygdala, septal regions, substantia innominata, and BST
were observed in pedophiles (Schiltz and others 2007).
Sexual interest in children was found to be associated
with lower white matter volumes of the superior fronto-
occipital fasciculus (Cantor and others 2008). Moreover,
central processing of visual sexual stimuli seems to activate
more strongly the subcortical regions involved in reward-
processing signals in homosexual pedophiles com­pared
with homosexual nonpedophiles (Schiffer and others
2008a). In a comparable study, heterosexual pedophiles
were found to show an activation of the dorsolateral pre-
frontal cortex instead of the normal orbitofrontal cortex
stimulation (Schiffer and others 2008b). These data indi-
cate an atypical brain development in pedophiles, leading
to atypical brain structures and processing in relation to
sexual behavior.
Neurobiology of Sexual Differentiation
in the Brain
As mentioned above, the direct effect of testosterone on
the developing brain is a main mechanism responsible for

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560 The Neuroscientist 16(5)
gender identity and sexual orientation in humans, which
has also been proved in different disorders. Complete
androgen insensitivity syndrome is caused by different
mutations in the gene for AR. The affected XY-males
develop as phenotypical women and experience “hetero-
sexual” orientation and fantasies without gender problems.
On the other hand, when a male fetus has a defi­ciency of
5a-reductase-2 or 17b-hydroxy-steroid dehydrogenase-3,
preventing peripheral testosterone from being transfor­
med into dihydrotestosterone, a “girl” with a large clitoris
will be born. These XY-children are generally raised as
girls. However, when testosterone production increases
during puberty, the “clitoris” grows into penis size and
testicles descend, the children’s build begins to masculin-
ize and becomes muscular. Despite that these children are
initially raised as girls, the majority (60%) will change
into heterosexual males, apparently by the organizing
effect of testosterone on early brain development and by
the activating effect of testosterone in puberty (for refer-
ences, see Swaab 2004; Swaab and Garcia-Falgueras
2009). Boys who are born with a cloacal exstrophy, that
is, with bladder exstrophy and partly or wholly absent penis,
are usually changed into girls immediately after birth. A
survey showed that in adulthood only 65% of these chil-
dren who were changed into girls continued to live as
girls, and when individuals with gender dysphoria were
excluded, the figure dropped to 47% (Meyer-Bahlburg
2005; Reiner and Gearhart 2004). These examples make
it clear that the direct effect of testosterone on the devel-
oping boys’ brain and a lack of effect on the developing
girls’ brain are crucial for the development of gender
identity and sexual orientation.
Sex Differences in Stress-
Coping Behavior
Stress as a psychological and biological term was first
coined in the 1930s by Hans Selye to refer to the conse-
quences of the failure of an organism—human or animal—
to respond appropriately to emotional or physical threats,
whether actual or imagined. In 1975, Selye further
divided stress into two major categories: eustress and dis-
tress (Selye 1975). Distress is referred to the persistent
stress that is not resolved through coping or adaptation
and, thus, may lead to anxiety or withdrawal (depression)
behavior. On the contrary, eustress is a positive stress that
motivates us via enhancing our physical or mental func-
tions. In either case, once we sense stressors, our bodies’
defenses kick into high gear in a rapid, automatic process
known as the stress response—“fight-or-flight.”
Clear sex differences are exhibited in stress-coping
behavior. Young human males, more than females, are
prone to risk-taking in relation to conflicts, outdoor
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activities, and car driving (Flisher and others 1993). In
addition, men are more likely to show physical aggression:
They commit 89% of all murders and 99% of all sexual
crimes (Spratt 2000), whereas women show more indirect
aggression such as targeting someone, spreading vicious
rumors about the target, gossiping behind this person’s
back, telling others not to associate with the intended vic-
tim, or even making up stories about that person (Hess
and Hagen 2006). Moreover, women are more expressive
of emotions (Caseras and others 2007), tend to score
higher on scales related to emotional experiences such as
neuroticism (Goodwin and Gotlib 2004), and have an
increased risk of suffering from depression and from most
anxiety disorders. Morphometric studies have shown sex-
ual dimorphism in several brain structures to be impli-
cated in emotional processing, such as the cingulate and
ventrolateral prefrontal cortices (larger in women) and
the medial temporal structures, including the amygdala
(larger in men; Goldstein and others 2001; Good and oth-
ers 2001; Paus and others 1996; Pujol and others 2002).
Both animal and human studies have shown that the female
brain’s innate strategy to handle stress differs from that of
the male brain (Taylor and others 2000; Ter Horst and
others 2009). Sex differences in stress regulation have
important implications for understanding physiological
differences in the male and female brain, and their impact
on vulnerability in disorders associated with stress.
Sex and Age Differences in the Brain
Stress-Coping System
The hypothalamo-pituitary-adrenal (HPA) axis is the key
system in the regulation of the stress responses. In brief,
the hypothalamus releases corticotropin-releasing hor-
mone (CRH) in response to a stressor, which triggers
the pituitary gland to secrete adrenocorticotropin (ACTH)
into the bloodstream and subsequently causes the release
of corticosteroid from the adrenal cortex (mainly cortisol
in humans). Cortisol as a major stress hormone also acts
on many other organs and brain circuits, such as the hip-
pocampus, amygdale, and prefrontal cortex, which also
participate in feedback regulation. In addition, cortisol
exerts a negative feedback effect on the pituitary and
hypothalamus to shut down the stress response after the
threat has passed, together with neurotransmitters such as
g-aminobutyric acid (Kovacs and others 2004). Part of
the CRH neurons in the hypothalamic paraventricular
nucleus (PVN) coexpress arginine vasopressin (AVP).
When released together into the portal capillaries, AVP
strongly potentiates the ACTH-releasing activity. In addi-
tion, circulating AVP from the supraoptic nucleus (SON)
may induce ACTH release from the pituitary (for refer-
ences, see Bao and others 2008).
Bao and Swaab 561

The HPA axis and autonomic responses tend to be

lower in women between puberty and menopause com-
pared with men of the same age. Roca and others have found
that young to middle-aged (18–45 years) men showed
increased stimulated ACTH and cortisol, in response to
either pharmacological (CRH) or physical (exercise)
stressors, compared with age-matched women. This result
was obtained in the absence of sex differences in estra-
diol or testosterone levels, because at the time of testing
the subjects underwent gonadal suppression with leupro-
lide acetate, a synthetic nonapeptide analog of naturally
occurring gonadotropin-releasing hormone but which
possesses greater potency than the natural one. In addi-
tion, the secretion of cortisol after exercise and the initial
secretion (0–30 min) of ACTH to either of the stressors
are significantly larger in this group of men than in
women. This shows that the sex differences exist even in
the absence of the characteristic differences in sex ste-
roids (Roca and others 2005). It has also been found that
in response to psychological stress the HPA axis is acti-
vated to a greater extent in elderly men than in women.
Cortisol production rate is clearly higher in men than in
women. Our group has also found gender differences in the
Figure 9. The total number of corticotropin-releasing
number of CRH-expressing neurons in the human hypo­
hormone (CRH)-immunoreactive neurons in the hypothalamic
thalamic PVN, namely: 1) There is a significant age- paraventricular nucleus (PVN) of control males () and
related increase of CRH neurons in men, but not in females (). The control males had significantly (P = 0.004)
women; and 2) men have significantly more CRH neu- more CRH neurons than control females from age 24 years
rons than women (Fig. 9). We also showed that an abnor- onward and showed a significantly positive correlation (the
mal hormone status, that is, by castration or ovariectomy solid line) between age and total number of CRH neurons.
or by a sex-hormone-producing tumor, was accompanied The control female group did not show significant correlation
(the dashed line) between age and total number of CRH
by changes in CRH neuron number (Bao and Swaab
neurons. Reprinted from Bao and Swaab 2007, copyright with
2007; Fig. 10). Age-related activation of CRH neurons permission from S. Karger AG, Basel.
could be affected by a series of factors, such as a decreased
function of the hippocampus, which suppresses the activ- least in part, be ascribed to the close functional interaction
ity of the HPA axis. A sex difference has also been reported between the HPA and the hypothalamo-pituitary-gonad
in hippocampal aging, for example, a significant age- (HPG) axes, and the fluctuation of circulating sex hor-
related decline of hippocampal volume was found in men mones in women, especially during menstruation, preg-
but not in women, which is consistent with our findings. nancy, after giving birth, and during the transition to
The posterior lobe of the pituitary is larger in boys than in menopause. Lower testosterone levels were also found in
girls, which is in agreement with the fact that men have severely depressed or dysthymic male patients. Men who
higher AVP levels than women. These sex differences have low total testosterone levels and a shorter CAG
also agree with the higher metabolic activity found in codon repeat length in the AR have a greater likelihood of
AVP neurons in the SON in young men as compared to becoming depressed, and supraphysiological doses of
women (for references, see Bao and others 2008). testosterone increased ratings of manic symptoms in men
(for references, see Bao and others 2008).
The higher prevalence of depression during a female’s
Sex Differences in Depression reproductive years especially during phases characterized
The HPA axis is considered to be the “final common by changes in hormone levels suggests that fluctuations
pathway” for a major part of the depressive symptom- of sex hormone levels play a more important role with
atology. Sex differences involving the regulation of the respect to the vulnerability for mood disorders than the
activity of the HPA axis take part in depression. Unipolar absolute basal levels. In this respect, it is of interest to
depression and dysthymia are twice as common in women find that female major depression (MD) patients did indeed
during their reproductive years as in men. This may, at have significantly higher amplitudes of diurnal estradiol

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562 The Neuroscientist 16(5)
Figure 10. The total number of corticotropin-releasing
hormone (CRH)-immunoreactive neurons in the hypothalamic
paraventricular nucleus (PVN) of control males and subjects
with abnormal sex hormone status.Values of control-male
group (, solid line), castrated-male group (∆, dashed line), and
“extended group,” that is, the castrated-male group (∆) plus an
ovariectomized female-to-male (F-M) transsexual (∇, dashed
line), are delineated by a minimum convex polygon. Note
that the total number of CRH neurons in the PVN of the 5
castrated males (n = 5, age ≥ 67 years) is significantly
(P = 0.008) lower than that of the matched older control males
(n = 5, age ≥ 66 years). Such a significant difference remained
(P = 0.009) when the ovariectomized F-M transsexual was
included in the “extended group” (n = 6, age ≥ 51 years)
compared with the matched control males (n = 6, age ≥
50 years). The total numbers of CRH neurons in the three
castrated-with-estrogen-replacement M-F transsexuals (ο)
were significantly larger than those in the castration group
(P = 0.036) and the “extended group” (P = 0.024), whereas there
was no significant difference when compared with age-matched
control males (age 50~70 years, n = 6, P = 0.905; or age 50~78
years, n = 5, P = 1.000). The 31-year-old male with an estrogen-
producing adrenal tumor () had a very high total number
(16,832) of CRH neurons in the PVN. M-F transsexual =
male-to-female transsexual; F-M transsexual = female-to-male
transsexual; Feminizing tumor = estrogen-producing adrenal
tumor. Reprinted from Bao and Swaab, copyright 2007, with
permission from S. Karger AG, Basel.
rhythms than controls (Bao and others 2004). In addition,
significant differences in the brain stress response cir-
cuitry were observed in different phases of the menstrual
cycle, illustrating that females have an inborn capacity to
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Figure 11. Frontal section of the paraventricular nucleus
(PVN) in a control (A, B) and a patient with mood disorder
(C, D) stained for corticotropin-releasing hormone (CRH; blue)
and ERa (red). B and D represent a 4× higher magnification of
A and C. The arrows, solid and hollow arrowheads, in A, B and
C, D indicate the same place in the preparation to facilitate
comparison. Both sections show the central part (midlevel) of
the PVN and contain the largest number of stained neurons.
It is clear by comparing A with C and B with D that the
number of stained neurons is markedly increased in this mood
disorder patient. III = the third ventricle. The arrow points
to an ERa nuclear single-staining cell; the solid arrowhead
points to a cytoplasmic CRH-ERa nuclear double-staining cell;
and the hollow arrowhead points to a CRH single-staining
cell. Reprinted from Bao and others, copyright 2005, with
permission from Oxford University Press.
regulate the stress response in a way that differs from
males (Goldstein and others 2010).
We have found colocalization of CRH and sex hor-
mone receptors, indicating a direct effect of sex hormones
on CRH neurons. Both the nuclear ERa (Bao and others
2005) and the nuclear AR (Bao and others 2006) are pres-
ent in CRH-expressing neurons in the human hypothalamic
PVN (Figs. 11, 12). In addition, a correlated up-regulation
of CRH and nuclear ERa was observed in mood disor-
ders, both in males and in females (Bao and others 2005).
It is known that the human CRH gene promoter contains
five perfect, half-palindromic estrogen-responsive ele-
ments (EREs), whereas animal studies have shown that
Bao and Swaab 563
Figure 12. Frontal section of the paraventricular nucleus
(PVN) in a subject stained for corticotropin-releasing
hormone (CRH; red) and androgen receptor (AR; blue). III =
the third ventricle. The upper-right corner represents a higher
magnification of the framed field and shows cytoplasmic
CRH (red) and AR (blue) nuclear double-staining neurons.
The arrow points to some AR single-staining cells. Bar in the
upper-right corner = 16 mm; in the lower right corner = 100
mm. Reprinted by permission from Macmillan Publishers Ltd:
Molecular Psychiatry, Bao and others, copyright 2006.
estrogens stimulate CRH production. We have also iden-
tified an androgen-responsive element (ARE) in the CRH
gene promoter region that initiates a repressing effect of
AR on CRH expression (Bao and others 2006), which is
in agreement with an animal study showing that andro-
gens inhibit CRH production (for references, see Bao and
others 2008). Recently, our group has observed a signifi-
cant increase of CRH-mRNA and ERa-mRNA and a sig-
nificant decrease of AR-mRNA in the PVN of mood
disorder patients (Wang and others 2008), which not only
supported the role of sex hormones in depression, but
also raised the possibility that a disturbed balance among
the factors affecting CRH activity may contribute to the
activation of the HPA axis, which is regarded as the final
common pathway for the pathogenesis of depression.
Conclusions
The human fetal brain develops in the male direction
through a direct action of testosterone and in the female
direction through the absence of such an action. During
the intrauterine period, gender identity, sexual orienta-
tion, and other behaviors are programmed in the brain in
a sexually dimorphic way. Sexual differentiation of the
genitals takes place before sexual differentiation of the
brain, which means that, in the case of equivocal genita-
lia at birth, the degree of genital masculinization may not
necessarily reflect the degree of masculinization of the
brain.
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There is no proof that the social environment has an
effect on the development of gender identity, sexual
orientation, or pedophilia. Structural sex differences of
hypothalamic nuclei or other brain areas in relation to
gender identity, and/or sexual orientation, indicate a
complex neuronal network involved in various aspects
of sexual behavior. Sex differences in the brain help us
to understand the nature of sex differences in behavior
and neuropsychiatric disorders, which will hopefully
help bring about sex-specific treatments and prevention
strategies.
Acknowledgments
We thank Mrs. W.T.P. Verweij for correcting the English and
Dr. Joe Normandin for his comments.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the authorship and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research and/or authorship of this article: Dr. A-M Bao is
supported by Nature Science Foundation of China (30970928)
and the Fundamental Research Funds for the Central Universi-
ties, China. Dr. A-M Bao and Dr. D.F. Swaab are supported by the
China Exchange Programme of the Royal Netherlands Academy
of Arts and Sciences (KNAW) (project 09CDP011).
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