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Sexual Identity and Sexual Orientation

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DOI: 10.1016/B978-0-12-803592-4.00104-8

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 5.12 Sexual Identity and Sexual Orientation
Laura Castellanos-Cruz, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and
Sciences, Amsterdam, The Netherlands
Ai-Min Bao, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang University School of Medicine,
Hangzhou, China; and Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
Dick F Swaab, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences,
Amsterdam, The Netherlands; Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang University School of
Medicine, Hangzhou, China; and Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine,
Hangzhou, China
Ó 2017 Elsevier Inc. All rights reserved.

5.12.1 Introduction 279

5.12.2 Sexual Differentiation of the Human Brain 279
5.12.2.1 Organizational Effects of Sex Hormones during Early Development and Activational Effects of Sex
Hormones in Puberty 280
5.12.2.2 Genetics and Epigenetics 281
5.12.3 Gender Identity and Sexual Orientation in Relation to Sex Differences in the Brain 282
5.12.3.1 Brain Development and Transsexuality 282
5.12.3.1.1 Genetics 282
5.12.3.1.2 Hormones 283
5.12.3.1.3 Postmortem Studies 283
5.12.3.1.4 Structural MRI 284
5.12.3.1.5 Functional MRI 285
5.12.3.2 The Brain and Sexual Orientation 285
5.12.3.2.1 Genetics, Epigenetics, and Hormones 285
5.12.3.2.2 Postmortem Studies 286
5.12.3.2.3 Positron Emission Tomography and MRI Studies 287
5.12.3.3 Pedophilia 287
5.12.4 Conclusions 288
Acknowledgments 288
References 288

5.12.1 Introduction
When we talk about a person’s sex, we are referring to their bio-
logical status, generally identified by sex chromosomes and/or
external genitalia. While biological sex is commonly thought of
as a binary state, either male or female, there are children who
are born with ambiguous genitalia that do not meet these clas-
sifications. For years the term ‘sex’ was interchangeable with
gender, a term that actually refers to the behaviors that a specific
culture associates with a specific sex. Someone’s gender identity,
their perceived-self as a male or a female can either be in line
with the cultural behavior associated with that sex or not, as
is the case in transsexual people. In some cases, a person iden-
tifies as ‘other’ or genderqueer, where they do not self-identify as
either sex or both. On the other hand, sexual orientation refers to
the sex that an individual is sexually or romantically attracted
to, and has also been commonly binary, heterosexual or homo-
sexual, if we neglect bisexuality. Gender identity that differs
from the cultural gender expectation and sexual orientation
and that moves away from this binary system has been a topic
of controversy and has even been pathologized with a psychi-
atric diagnosis. Until the 1970s, the American Psychiatric Asso-
ciation listed homosexuality as a mental disorder in its
Diagnostic and Statistical Manual of Mental Disorders (DSM) II.
In the recent publication of the DSM V, gender variance is
contemplated in the gender dysphoria (GD) diagnosis, but is
still a cause for conflict due to its label of ‘mental disorder.’
In this chapter, our aim is to present the current neurobiolog-
ical hypotheses explaining gender identity and sexual orienta-
tion and to evaluate the findings in studies regarding these
hypotheses.
5.12.2 Sexual Differentiation of the Human Brain
Although meta-analyses show that men and women – or boys
and girls – behave similarly (Hyde, 2005), we can find evident
sex differences expressed in human behavior from the first day
of life onward. Female babies prefer looking at human faces,
while male neonates prefer mechanical mobiles (Connellan
et al., 2000). Girls of 3–8 months prefer playing with dolls
while boys prefer vehicles, a behavior observed also in
nonhuman primates (Alexander and Hines, 2002, Hassett
et al., 2008). This indicates the involvement of an evolutionary
old mechanism. Also, when spontaneous drawings by children
aged 5–6 are evaluated, girls tend to draw human motifs,

Hormones, Brain, and Behavior, 3rd edition, Volume 5 http://dx.doi.org/10.1016/B978-0-12-803592-4.00104-8 279

280 Sexual Identity and Sexual Orientation
flowers, and butterflies in light warm colors arranged in a row,
while boys tend to draw means of transportation, soldiers, and
fighting from a bird’s eye view and in darker colors (Iijima
et al., 2001). This sexually dimorphic behavior has been asso-
ciated with different prenatal testosterone levels. Girls with
congenital adrenal hyperplasia (CAH), who were exposed to
high testosterone levels prenatally, prefer toys that are usually
preferred by boys. CAH girls also have more boy playmates,
create drawings similar to male children, and exhibit some
male-typical personality features (Iijima et al., 2001; Mathews
et al., 2009). On the other hand, XY individuals with complete
androgen insensitivity syndrome (CAIS) due to a mutation in
the androgen receptor (AR), who perceive themselves as hetero-
sexual women, recall having reduced male-typical and
increased female-typical play behavior in childhood (Hines,
2008).
5.12.2.1 Organizational Effects of Sex Hormones during Early
Development and Activational Effects of Sex Hormones in
Puberty
The phenotype of the human embryo is bipotential. In XY indi-
viduals, sexual differentiation starts prenatally with the viriliz-
ing effects of testosterone, and by this virilizing effect, we
obtain sexual differentiation (Reiner and Reiner, 2012). The
gonads develop under the influence of a cascade of events
that starts, in XY babies, with the sex-determining gene in the
Y chromosome (SRY) (Ngun et al., 2011). SRY determines
the formation of testes, and in its absence, ovaries are formed
(Rice et al., 2012). Testosterone secretion (by the testes) and
its peripheral conversion to dihydrotestosterone (DHT), both
required for the formation of the male external genitalia
(Reiner and Reiner, 2012), starts between weeks 6 and 12 of
pregnancy (Wilson et al., 1981; Bao and Swaab, 2011). Because
of the testicular secretion, male fetuses have significantly higher
average testosterone levels than females, whose testosterone
originates only from fetal adrenals and from placental/
maternal sources. Although the average testosterone levels in
males are higher, there is always an overlap of testosterone
levels between males and females which causes some females
to have higher testosterone levels than males at all time points
(Rice et al., 2012), suggesting that a difference in sensitivity to
testosterone determines sexual differentiation rather than the
absolute testosterone level (Rice et al., 2012). Sexual differenti-
ation takes place during the second half of pregnancy (and
early postnatal in nonhuman male mammals) under the influ-
ence of testosterone. The effects of hormones on the developing
brain are referred to as organizational effects and are generally
permanent and irreversible. During puberty, these circuits are
activated, also under the influence of sex hormones.
Testosterone has a direct involvement in gender identity
and sexual orientation by its effect in the developing human
brain (Bao and Swaab, 2011). Much of the information on
the mechanisms of testosterones’ effects comes from studies
on nonhuman mammals. Crucial information has also been
obtained from conditions in which individuals are exposed
to abnormal hormone levels or have a different sensitivity to
hormones prenatally, such as XY individuals with CAIS
(Swaab, 2004; Hines, 2008; Bao and Swaab, 2011; Rice et al.,
2012). Currently, in humans, we only have evidence of
testosterone influencing brain sexual differentiation. However,
it has been shown in mouse models that the feminization of
the brain occurs during prepubertal development under the
influence of estrogens (Bakker and Brock, 2010). Studies on
women with Turner Syndrome, a condition where part of or
a complete X chromosome is missing and that presents with
ovarian dysgenesis, have shown that these women report lower
heterosexual behavior. The combination of these findings
suggests the need to explore the role of estrogens on the sexual
differentiation of the human brain (Burke and Bakker, 2015).
CAH is caused by a mutation in the CYP21A2 gene. As
mentioned above, individuals with CAH are exposed to
elevated androgens prenatally. This recessive autosomal disease
causes a deficiency of 21-hydroxylase, an enzyme needed for
the production of cortisol. The inability to produce cortisol
results in an excessive production of androgens and presents
with genital ambiguity in XX newborns. There is a wide range
of severity levels in the phenotypical presentation of CAH,
depending on the impairment level of 21-hydroxylase. The
classic or severe form is caused by a high deficiency of the
enzyme, with a prevalence of 1 in 16 000 births (Merke and
Poppas, 2013). Although most of these girls are reared as
females, they have increased male-typical play behavior (Hines,
2008; Hines et al., 2015). Additionally, 30% of CAH girls are
homosexual or bisexual, and 5% of them have GD – an inci-
dence that is 100–300 times higher than the general popula-
tion (Meyer-Bahlburg et al., 1996; Hines et al., 2004; Reiner
and Reiner, 2012).
XY individuals with CAIS, caused by different mutations in
the AR gene, have normally functioning testes, but an inability
to respond to the produced androgens, thus they develop
phenotypically as women. They present with a standard onset
of puberty, for girls, but without menses. These individuals
report a high self-perceived feminity and a female heterosexual
orientation (Wisniewski et al., 2000). Also, as mentioned, they
recall more female-typical play behavior in childhood (Hines,
2008; Bao and Swaab, 2011). These data suggest the impor-
tance of testosterone sensitivity in the establishment of
perceived gender and orientation.
When an XY fetus has a 17b-hydroxy-steroid-dehydroge-
nase-3 (17b-HSD3) deficiency, the enzyme that converts 4D-
androstenedione (4D-A) to testosterone, the child is most
commonly born with female external genitalia with or without
clitoromegaly. In these individuals, the enzyme can be missing,
reduced or inactive. These children are generally raised as girls.
During puberty, the testosterone production increases, prob-
ably due to peripheral conversion of 4D-A mainly by other
isoenzymes (Faienza and Cavallo, 2012), the ‘clitoris’ grows
to a normal penis size, the testes descend, they become more
muscular with more body hair and their voice deepens (Bao
and Swaab, 2011; Faienza and Cavallo, 2012). Similarly
a 5a-reductase-2 (5a-RD-2), the enzyme needed to convert
testosterone into DHT during fetal development, deficiency
also results in a lack of masculinization of external genitalia.
During puberty, the virilization of these individuals occurs
probably by an increase of 5a-reductase-1, which then converts
testosterone into DHT (Cohen-Kettenis, 2005; Bao and Swaab,
2011). Despite the fact that these children are reared as girls,
the majority of them (60%) will choose to live as heterosexual
males (Cohen-Kettenis, 2005; Faienza and Cavallo, 2012),

apparently due to the organizing effect of testosterone in early
brain development and the activating effect of testosterone in
puberty (Bao and Swaab, 2011).
Cloacal exstrophy is a developmental defect in the embryo-
genesis of the pelvis. It has an incidence of 1 in 400 000 live
births and presents, among other aspects, with bladder exstro-
phy, short gut syndrome, and absent or severely malformed
genitalia. Because aphallia (absence of a penis) is frequent,
gender reassignment has been the usual treatment for XY
babies with cloacal exstrophy (Reiner and Gearhart, 2004;
Gordetsky and Joseph, 2015). Female genitalia are surgically
constructed, and orchiectomy is performed. These children
are brought up as female, but in the long term the majority
of them identify as male (Reiner and Gearhart, 2004). A study
of 60 individuals with aphallia showed that 36 (60%) had
transitioned from female to male and expressed attraction to
females. The remaining 24 (40%) were unwilling to discuss
sexual orientation (Reiner and Reiner, 2012).
Endocrine disrupters, e.g., certain pesticides, herbicides,
plastic contaminants (such as phthalates), pharmaceuticals
(such as diethylstilbestrol (DES)), and dietary components
(such as phytoestrogens), are compounds present in the envi-
ronment, which may pass the placenta and intervene in the
interaction between endogenous sex hormones and the devel-
oping brain. Prenatal exposure to phthalates, an antiandro-
genic in plastics, is associated with less male-typical behavior
in boys (Swan et al., 2010). Intrauterine exposure to mild anal-
gesics, which are antiandrogenic prostaglandin inhibitors, is
a risk factor for the development of male reproductive disorders
(Kristensen et al., 2011). Moreover, boys whose mothers were
exposed during pregnancy to pesticides have smaller testicular
volume and penile length at the age of 6–11 than nonexposed
boys, while girls showed earlier breast development
(Wohlfahrt-Veje et al., 2012a,b). The implications of these find-
ings on gender identity and sexual orientation are still to be
studied.
5.12.2.2 Genetics and Epigenetics
In addition to sex hormones, sex chromosomes and genes also
have a direct influence in brain sexual differentiation. As
mentioned earlier, SRY is one of the most studied genes for
this action. Most of the sex differences studied are dependent
on gonadal hormones; however, studies aimed at isolating
the effect of sex hormones and sex chromosomes have shown
that some brain sex differences or sexual behaviors are deter-
mined by sex chromosomes, independent of gonadal
hormones. Some sex differences determined alone by sex chro-
mosomes are the higher expression of tyrosine hydroxylase in
midbrain neurons of XY mice (Carruth et al., 2002) and the
sexual behavior in female mice (Grgurevic et al., 2012) (for
a complete review, see Forger et al., 2016).
A study evaluating gray matter (GM), white matter (WM),
and sex hormone levels of XXY individuals, together with XY
and XX healthy human controls, found that sex differences in
the precentral gyrus and cerebellum were linked to the number
of X chromosomes, i.e., XXY individuals had a bigger precentral
gyrus and parietal cortex and a smaller hypothalamus and cere-
bellum when compared to XY or XX individuals (Lentini et al.,
2013). There are also reports of smaller precentral GM and
Sexual Identity and Sexual Orientation 281
larger temporal GM volume in XO women compared to XX
women (Marzelli et al., 2011). Testosterone was associated
with a larger occipital GM volume in men and other regions
with previously documented sexual dimorphism. No specific
association was found between the volumes of these brain
areas and the Y chromosome, except for its relation to testos-
terone (Lentini et al., 2013). In addition, it was found that
50 genes expressed in fetal mouse brain show clear, different
levels for males and females, even before sex hormones come
into play (Dewing et al., 2003).
In the last decade, we have come to realize the role of the
epigenetic regulation of these genes in the sexual differentiation
of the brain. ‘Epigenetics’ refers to changes in gene expression
without changes in the DNA sequences. Gene expression is
modulated by modifications in the chromatin, which result
in new cellular phenotypes with the same genotype. Epigenetic
changes may occur in response to the genome, the environ-
ment, drug exposure, and experience (McCarthy et al., 2009;
Lv et al., 2013; McCarthy and Nugent, 2013; Piferrer, 2013).
Epigenetic regulation is achieved through at least four types
of modifications: methylation of DNA, modification of
histones, imprinting, and micro RNAs (McCarthy and Nugent,
2015). The process by which early exposure to gonadal
hormones organizes the brain and creates the ‘cellular
memory,’ which elicits a sexual dimorphic response in adult-
hood, is thought to occur through epigenetic modifications
(McCarthy et al., 2009; Forger, 2016). In the nervous system,
these modifications regulate neurogenesis, gliogenesis, and
neural apoptosis (Lv et al., 2013). In addition, they control
synaptic plasticity and therefore are involved in memory and
learning (Guan et al., 2015). Epigenetic mechanisms also regu-
late sexual differentiation of the brain and are involved in the
regulation of social, maternal, and sexual behavior (Krishnan
and Nestler, 2008; Auger and Auger, 2011; Matsuda et al.,
2011, 2012; Vialou et al., 2013; McCarthy and Nugent, 2015;
Forger, 2016).
The most studied epigenetic modifications are DNA methyl-
ation and changes in histones (McCarthy et al., 2009; Forger,
2016), both required for sexual differentiation of the brain
during development and/or are sexually dimorphic in the brain
(McCarthy et al., 2015; Forger et al., 2016). Although the often
seen changes in histones are the methylation and/or acetylation
of the protruding tails, phosphorylation, ubiquitination, and
sumoylation may also take place (McCarthy et al., 2009). The
human central nucleus of the bed nucleus of the stria terminalis
(BSTc) is sexually dimorphic, with males having a greater
volume and number of cells than females (Zhou et al., 1995;
Kruijver et al., 2000). Inhibition of histone deacetylases
(HDACs) with valproic acid prevented the levels of histone 3
(H3) acetylation from increasing during a critical period for
brain sexual differentiation and masculinization of the BSTc
in rodents (Murray et al., 2009). Intraventricular injection of
HDACs inhibitors also suppressed male sexual behavior (Mat-
suda et al., 2011). Shen et al. (2015) found 248 genes and loci
in the rodent BST and preoptic area (POA) with sex differences
in histone 3-lysine-4 trimethylation (H3K4me3). The genes
and loci with increased H3K4me3 in females were associated
with synaptic function (Shen et al., 2015). DNA methylation
involves the addition of a methyl group to the 50 carbon of
cytosines that are located next to guanines (mCpG) and is
282 Sexual Identity and Sexual Orientation
regulated by DNA methyltransferases (DNMTs). Methylated
cytosines can then recruit other proteins, such as methyl-
CpG-binding protein 2 (MeCP2), which can then attract
HDACs. DNA methylation is needed for cellular differentia-
tion, suppression of the repetitive elements in nucleic acids,
imprinting and inactivation of the X chromosome (Vialou
et al., 2013). Reduction of MeCP2 expression in the amygdala
of neonatal rats reduced social play behavior in males and
eliminated the usual sex difference in playing behavior (Kurian
et al., 2008). Female rats have more DNMT activity and more
methylated sites in the POA. The sex differences in juvenile
social play behavior were eliminated when the rats were treated
with estradiol and sexual behavior in the female rats was
masculinized, suggesting that brain feminization was main-
tained by suppressing masculinization through DNA methyla-
tion (Nugent et al., 2015). Epigenetic alterations in the human
brain in relation to gender identity and sexual orientation now
have to be studied.
It is evident that the process and regulation of sexual differ-
entiation of the brain has multiple mechanisms, paths, and
endpoints. Different brain structures have different ways of
achieving sexual differentiation, while some brain areas seem
to have no sexual dimorphism. Interaction of genes, sex
hormones, and developing brain cells are thought to provide
the basis for behavior, gender identity, and sexual orientation.
The complex process of sexual differentiation of the brain
ensures variability, but also provides multiple points that can
be disrupted or modified, which may permanently influence
these behaviors.
5.12.3 Gender Identity and Sexual Orientation in
Relation to Sex Differences in the Brain
From the age of 2 years, sex differences in brain weight are
already present in terms of allometric relation to body size
(Swaab and Hofman, 1984). In the adult brain, structural sex
differences have also been observed. Anatomically, cerebral
sex differences are present both in GM and WM compartments,
even when correcting for individual differences in total brain
volume (Lentini et al., 2013). The hippocampus, caudate
nucleus, and anterior cingulate gyrus of women tend to have
a larger volume. In men, the amygdala is larger. In general,
men have larger GM volumes in the mesial temporal lobe,
the cerebellum, and the lingual gyrus, and women have larger
GM volumes in the precentral gyrus, the anterior cingulate, the
right inferior parietal, and the orbitofrontal cortex (Lentini
et al., 2013). Many neuropsychiatric illnesses that have an
evident skewed sex distribution are associated with cerebral
areas that differ among healthy male and female individuals
(Lentini et al., 2013). Our group was the first to find a structural
sex difference in the human hypothalamus, i.e., in the sexually
dimorphic nucleus of the preoptic area (SDN-POA). The SDN-
POA, also called intermediate nucleus or interstitial nucleus
of the anterior hypothalamus (INAH)1 (Swaab and Garcia-
Falgueras, 2009), of men was found to be 2.5 times larger
and to contain 2.2 times more cells than that of women
(Swaab and Fliers, 1985).
In the 1960s and 1970s the general assumption was that
a child is born as a tabula rasa and that rearing determines
the individual’s gender identity. John Money stated that
“Gender 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 experi-
ences of rearing” (Money, 1975; Bao and Swaab, 2011). This
view had devastating results in the case of David Reimer, the
John-Joan-John case, in which, based upon Money’s view, an
8-month old boy, who lost his penis during a minor surgical
procedure, was surgically reassigned as a girl. Reimer was orchi-
ectomized and reared as female. He was given ‘girl’s’ toys and
received psychological counseling and, when he reached
puberty, was given estrogens. According to Money, this child
developed and identified as female. However, it became known
later that Reimer never did identify himself as female and had
resumed his life as a male when he was 14 years old (Diamond,
2004). After years of severe depression, financial instability,
and a dissolving marriage, Reimer committed suicide in
2004. This story illustrates the strength of the irreversible
programming of the brain concerning gender identity during
the intrauterine period.
5.12.3.1 Brain Development and Transsexuality
GD or transsexualism refers to the desire to live and be identi-
fied as a member of the opposite sex and is frequently accom-
panied by a feeling of having an inappropriate anatomical sex,
wishing to be as congruent as possible with the gender one
identifies with. This eventually leads to a request for hormonal
therapy and/or sex reassignment surgery (Bao and Swaab,
2011; Mandal and Jakubowski, 2015). Clinically, there are
two fundamentally different types of GD: early-onset GD and
late-onset GD. Individuals with early-onset GD, also referred
to as homosexual transsexualism, are sexually attracted to other
individuals of their natal sex; late-onset GD, also referred as
nonhomosexual GD, presents a variable sexual orientation
and symptoms which start during or after adolescence (Burke
and Bakker, 2015). Although there is not one specific etiolog-
ical factor, the current hypothesis is that there is a sex-atypical
cerebral programming, different from the natal sex. This atyp-
ical programming could be caused by multiple elements,
including effects of hormones and genetic factors, such as poly-
morphism of genes encoding elements of sex steroid signaling
or metabolic pathways (Heylens et al., 2012).
Factors associated with GD are summarized in Table 1.
5.12.3.1.1 Genetics
A study of 314 twins found a high heritability (62%) of GD,
with a 2.6% prevalence of GD in these twin samples (Coolidge
et al., 2002). Fernandez et al. conducted a study in 273
untreated, early-onset female-to-male transsexuals (FtM-TR)
exploring the variable gene regions of the sex hormone-
related genes, including estrogen receptor (ERb), AR, and
aromatase (CYP19A1). They observed that FtM-TR differed
from the control group with regard to the median length of
ERb, differentiating between two alleles: short (S) and long
(L). The greater number of CA repeats in this gene implied
greater transcriptional activation and lower feminization or
greater defeminization. Subjects with a genotype of
homozygous LL for the ERb gene have a greater probability
for FtM transsexualism than those who are heterozygous LS

Table 1 Factors associated with the etiology of GD
Etiology
Genetic Twin studies (Coolidge et al., 2002)
Polymorphisms in ERb, androgen receptor, and
aromatase genes (Fernandez et al., 2014b)
Hormones Phenobarbital/diphantoin taken by pregnant mother
(Dessens et al., 1999)
Cloacal exstrophy (Reiner and Gearhart, 2004; Reiner and
Reiner, 2012)
17b-Hydroxy-steroid-dehydrogenase-3 deficiency
(Faienza and Cavallo, 2012)
(Bao and Swaab, 2011)
5a-Reductase-2 deficiency (Cohen-Kettenis, 2005; Bao
and Swaab, 2011)
Girls with CAH (Meyer-Bahlburg et al., 1996; Hines et al.,
2004; Hines, 2008; Reiner and Reiner, 2012; Merke and
Poppas, 2013)
Complete androgen insensitivity syndrome in XY
individuals (female phenotype, female gender identity)
(Wisniewski et al., 2000; Hines, 2008; Bao and Swaab,
2011)
DES? (Kerlin, 2005)
Immunological Fraternal birth order effect (Schagen et al., 2012)
Abbreviations: CAH, congenital adrenal hyperplasia; DES, diethylstilbestrol; MtF-TR, male-to-female transsexuals; FtM-TR, female-to-male transsexuals; GD, gender
dysphoria; ER, estrogen receptor.
or homozygous SS (Fernandez et al., 2014b). However, studies
in male-to-female transsexuals (MtF-TR) analyzing these same
genes did not show a possible relationship between these genes
and the development of MtF transsexualism (Fernandez et al.,
2014a).
5.12.3.1.2 Hormones
Although most XX individuals with CAH have no GD, they
have a 100–300 times higher risk of transsexuality than the
controls (Bao and Swaab, 2011). When given to pregnant
women, phenobarbital and diphantoin (antiepileptic drugs)
also present an increased risk of giving birth to a transsexual
child. These drugs may change the metabolism of sex
hormones and thus affect sexual differentiation of the child’s
brain (Dessens et al., 1999).
Between 1939 and 1960, 2 million pregnant women in the
United States and Europe were prescribed DES, an estrogen-like
drug meant to prevent miscarriage. However, not only did DES
not prevent miscarriage, but also it seems that male offspring
of women exposed to DES during pregnancy had a higher prev-
alence of GD (Kerlin, 2005). It should be noted that there are
some studies that did not find this relationship (Newbold,
1993; Titus-Ernstoff et al., 2003).
Furthermore, homosexual MtF-TR individuals were found
to have a later birth order and more brothers than sisters,
suggesting the presence of immunological processes during
pregnancy, directed toward products of the Y chromosome
(Schagen et al., 2012). This suggests some external prenatal
factor can have some influence of GD development.
5.12.3.1.3 Postmortem Studies
Postmortem studies have been performed in order to find
structural evidence which may corroborate the hypothesis of
Sexual Identity and Sexual Orientation 283
Findings
62% heritability, 2.6% prevalence of GD
[ probability of FtM-TR in individuals homozygous for
long allele of ERb. No evidence for MtF-TR
[ rates of cross-dressing and/or GD
Cross-sex rearing did not change gender identity
Cross-sex rearing did not change gender identity
Cross-sex rearing did not change gender identity
[ incidence of GD (100–300 times higher)
XY individuals with female gender identity
[ incidence of GD in exposed male individuals?
MtF-TR tend to have more siblings and later birth order
than controls
a sex-atypical cerebral programming for GD. Our group has
observed some reversals in brain areas of GD subjects, in
the BSTc and the interstitial nucleus of the anterior
hypothalamus-3 (INAH3), both of which are involved in
sexual behavior in rodents. The BSTc volume in men is twice
as large as in women, and it contains twice as many
somatostatin-expressing neurons (Figure 1). The same is
true for the INAH3, which was found to be 1.9 times larger
and to contain 2.3 times more neurons in men than in
women. In addition, a female INAH3 and BSTc have been
found in MtF-TR. The only FtM-TR available for our study
had a BSTc and INAH3 with clear male characteristics. These
sex reversals were found not to be influenced by circulating
sex hormone levels in adulthood and seem to have arisen
during development (Zhou et al., 1995; Kruijver et al.,
2000; Garcia-Falgueras and Swaab, 2008). Moreover, we
found that MtF-TR showed a female-typical expression of
neurokinin B, a regulator of gonadotropin-releasing
hormone (GNRH) release in the hypothalamus (Taziaux
et al., 2012).
Brain structures have also been studied in vivo in transsex-
uals. Studies have shown ‘masculinization’ of WM of the right
superior longitudinal fascicule (SLF) and the right corticospinal
tract (CST) in adult FtM-TR when compared to control females.
The differences were found before cross-sex hormonal
(testosterone) treatment and were intensified after treatment,
suggesting that testosterone also changed the WM
microstructure (Rametti et al., 2011a, 2012). In untreated
MtF-TR, the WM microstructure of both the right and left
SLF, the CST, the forceps minor, and the cingulum were all
found to differ from the natal sex and fell in an intermediate
position compared with male or female controls (Rametti
et al., 2011b).
284 Sexual Identity and Sexual Orientation

(a) (b)

(c) (d)

Figure 1 Left: Representative sections of the central nucleus of the bed nucleus of the stria terminalis (BSTc) innervated by vasoactive intestinal
polypeptide. (a) heterosexual man; (b) heterosexual woman; (c) homosexual man; (d) male-to-female transsexual. Scale bar ¼ 0.5 mm. LV ¼ lateral
ventricle. Note there are 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. Right: Distribution
of the BSTc neuron numbers among the different groups according to sex, sexual orientation, and gender identity. M ¼ heterosexual male reference
group; HM ¼ homosexual male group; F ¼ female group; TM ¼ male-to-female transsexuals. The sex hormone disorder patients S1–6 and M2 indi-
cate 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) becomes also statistically significant according to the sequential Bonferroni 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.
Whether the transsexuals were male oriented (T1, T6), female oriented (T2, T3, T5), or both (T4) did not have any relationship with the neuron
number of the BSTc. The same holds true for heterosexual and homosexual men. This shows that the BSTc number of somatostatin neurons is not
related to sexual orientation. A ¼ 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 ¼ postmenopausal woman. S1
(\ 46 years of age): adrenal cortex tumor for more than 1 year, causing high cortisol, androstendione, and testosterone levels. S2 (\ 31 years of
age): feminizing adrenal tumor that induced high blood levels of estrogens. S3 (_ 67 year of age): prostate carcinoma; orchiectomy 3 months before
death. S5 (_ 86 years of age): prostate carcinoma; prostatectomy; orchiectomy, and antiandrogen treatment for the last 2 years. S6 (\ 25 years of
age): Turner syndrome (45,X0; ovarian hypoplasia). M2 (\ 73 years of age): postmenopausal status. Used with permission from Kruijver, F.P.M.,
Zhou, J.-N., Pool, C.W., Hofman, M.A., Gooren, L.J.G., Swaab, D.F., 2000. Male-to-Female transsexuals have female neuron numbers in a limbic
nucleus. J. Clin. Endocrinol. Metab. 85, 2034–2041.

5.12.3.1.4 Structural MRI They did not find ‘feminization’ or ‘masculinization’ of

Neuroimaging studies of GM have found different results,
some in line with biological sex and others with identified
gender (Savic and Arver, 2011; Simon et al., 2013; Zubiaurre-
Elorza et al., 2013). It should be noted that matching these
studies in terms of methodology and/or subjects is difficult.
Methodological differences may provide different results, while
studies including early-onset or late-onset GD subjects with
different sexual orientation and/or treatment may further inter-
fere with the results. Manzouri et al. proposed a hypothesis sug-
gesting that GD is caused by alterations in functional and
structural networks that involve the own-body perception.
different brain structures, but they did observe changes in these
networks (Savic and Arver, 2011; Manzouri et al., 2015) – the
untreated FtM-TR and MtF-TR have smaller thalamus and
putamen volumes in relation to either male or female
controls. MtF-TR had greater GM volumes in the right insular
and inferior frontal cortex, while FtM-TR had greater GM
volumes in the right occipitoparietal junction and the inferior
frontal gyrus. In addition, FtM-TR had weaker functional
connections from the pregenual anterior cingulate to the
insular cortex and to the temporoparietal junction (Savic and
Arver, 2011; Manzouri et al., 2015). A recent study evaluating
 Sexual Identity and Sexual Orientation 285

regional volumes and spatial volumetric distribution of GM
found no differences between transsexual individuals and
controls when comparing GM volumes in the whole brain.
However, they did find variable GM volumes when analyzing
regions of interest in sexually dimorphic areas. FtM-TR had
statistically significant greater GM volumes in the right
cerebellum, and a smaller volume in the left superior and
medial frontal cortex when compared to female controls.
MtF-TR had statistically significantly smaller GM volumes in
left cerebellum and hypothalamus in line with their gender
identity, suggesting a sex-atypical differentiation of the brain
(Hoekzema et al., 2015).
5.12.3.1.5 Functional MRI
Functional MRI (fMRI) studies also suggest a sex-atypical
brain programming. Nontreated MtF-TR had a female-like
tendency of cerebral activation when exposed to visual erotic
stimuli (Gizewski et al., 2009). In a study measuring brain
activation in adolescents while performing verbal fluency
tasks, MtF-TR performed the tasks better than both control
girls and boys. However, boys had a higher activation in the
right Rolandic operculum than girls, but no significant
difference in brain activation between GD adolescents was
found. However, a subthreshold activation showing a linear
increase (from lowest to highest) was noted in this area
when performing verbal fluency tasks from girls (lowest)-
FtM-MtF-boys (highest) (Soleman et al., 2013). In a mental
spatial rotation task, the brain activation of MtF-TR showed
a divergence from the natal sex in the recruitment of parietal
regions involved in this function (Schoning et al., 2010).
There is a sexually dimorphic activation of the hypothal-
amus of men and women when exposed to different concentra-
tions of androstadienone, which is secreted in axillary sweat
and is associated with sexual motivation (Burke et al., 2012).
Prepubertal and adolescent boys showed a stable activational
response when smelling androstadienone, which declined
with exposure, while prepubertal and adolescent girls showed
an increased response with exposure. The results of the prepu-
bertal group of GD boys were similar to controls of their natal
genders, while those of GD girls did not differ from those of
either boys or girls. In contrast, the GD adolescents responded
in a similar way to their respective genders with whom they
identified. These results suggest not only a sex-atypical brain
programming but also the involvement of pubertal sex
hormones in the expression of GD. The result obtained in the
prepubertal group could be explained by the fact that only
20% of children with GD symptoms will actually have GD in
adulthood, and women have an earlier onset of GD (Burke
and Bakker, 2015).
5.12.3.2 The Brain and Sexual Orientation
As mentioned above, sexual orientation refers to the sex one is,
sexually or romantically, attracted to, i.e., to the opposite sex
(heterosexual), the same sex (homosexual), or both sexes
(bisexual). Homosexuality is common in the human popula-
tion, with a prevalence of around 8% for both sexes (Bailey
et al., 2000). Sexual orientation is also determined during brain
development, by genetic factors that influence the interaction
between sex hormones and the developing brain, and it
becomes evident during puberty under the activating influence
of sex hormones. Men’s sexual orientation tends to be more
bimodal (heterosexual vs homosexual) than women’s sexual
orientation, which have higher rates of bisexuality and less
temporal stability (Bailey et al., 2000; Ngun et al., 2011;
Sanders et al., 2015). Factors involved in homosexuality are
summarized in Table 2.
5.12.3.2.1 Genetics, Epigenetics, and Hormones
Epidemiological genetic studies indicate that the development
of sexual orientation is largely familial (Bailey and Bell, 1993;
Sanders et al., 2015), and an independent familial aggregation

Table 2 Factors associated with the etiology of sexual orientation

Etiology Findings

Genetic Epidemiological studies (Bailey and Bell, 1993; Sanders
et al., 2015)
Linkage inheritance (Hamer et al., 1993; Sanders et al.,
2015)
Sexual antagonistic inheritance (Camperio-Ciani et al.,
2004; Bocklandt et al., 2005; Iemmola and Camperio
Ciani, 2008; Ciani et al., 2015)
X chromosome skewed inactivation (Bocklandt et al.,
2005)
Hormones Girls with CAH (Meyer-Bahlburg et al., 1996; Hines et al.,
2004; Meyer-Bahlburg et al., 2007; Reiner and Reiner,
2012)
Prenatal exposure to nicotine, amphetamines or thyroid
medication (Ellis and Cole-Harding, 2001; Ellis and
Hellberg, 2005)
Immunological Fraternal birth order effect (Bogaert and Skorska, 2011;
Ngun et al., 2011)
8% prevalence for both sexes
[ incidence in biological relatives of homosexual men
[ concordance in identical twins vs fraternal twins
Two regions of linkage: pericentromeric on chromosome
8 and in Xq28 to male homosexuality
Increased fecundity (33%) in ascending female relatives of
male homosexual individuals
Larger families and number of older brothers in
homosexual individuals
10–20% higher skewing of X inactivation in mothers of
homosexual individuals
[ incidence of homosexuality or bisexuality in girls
[ incidence of female homosexuality
Male homosexuals have more older brothers than controls

Abbreviations: CAH, congenital adrenal hyperplasia.

286 Sexual Identity and Sexual Orientation
of female and male homosexuality has been noted, suggesting
the importance of separate analysis by sex (Sanders et al.,
2015). Male homosexuality is more common in biological rela-
tives of homosexual men compared to heterosexual men (or
the general population) and has a higher incidence between
identical twins than same sex fraternal twins (Sanders et al.,
2015). A number of genetic studies have suggested an excess
of maternal transmission (X-linked inheritance). The X
chromosome has accumulated genes involved in sex,
reproduction, and cognition. A meta-analysis of four linkage
studies suggests that Xq28 may indeed play an important role
in male homosexuality (Hamer et al., 1993). Although some
later studies did not find evidence of such a linkage, a recent
genome-wide linkage scan of 908 samples found a significant
linkage of male homosexuality to the pericentromeric region
on chromosome 8 and the study also replicated the linkage
for Xq28 (Sanders et al., 2015).
Ascending females in the maternal line of male homosexual
probands produce approximately 33% more offspring than
females in the maternal line of heterosexuals (Camperio-
Ciani et al., 2004). Homosexual men tend to have larger fami-
lies and a higher number of older brothers (Blanchard, 1997;
Iemmola and Camperio Ciani, 2008). Since there is no
increased paternal fecundity in homosexual relatives, it is
possible that there is a sexually antagonistic inheritance, partly
linked to the X chromosome, which promotes fecundity in
females and homosexual orientation in males (Camperio-
Ciani et al., 2004; Iemmola and Camperio Ciani, 2008). X inac-
tivation is associated with gene silencing by DNA and/or
histone methylation. A study found that women with homo-
sexual sons had an extreme skewing of X inactivation (13%)
compared to mothers without homosexual sons (4%), and in
mothers with two or more gay sons this ratio was even higher
(23%) (Bocklandt et al., 2005).
The ‘fraternal birth order effect’ is a finding that has been
most frequently replicated when studying homosexuality in
men, as the more elder brothers a man has, the higher the
odds for male homosexuality. Each elder brother increases
the odds for male homosexuality by 33%, but this only goes
for brothers from the same mother (Ngun et al., 2011). It is
hypothesized to be caused by antibodies against male-specific
antigens (for review, see Bogaert and Skorska, 2011).
Prenatal sex hormones also play a role in sexual orientation.
As mentioned, girls with CAH have a higher prevalence of
bisexual and homosexual orientation than the rest of the pop-
ulation (Meyer-Bahlburg et al., 1996; Hines et al., 2004; Reiner
and Reiner, 2012). When comparing women with classic CAH,
who are further grouped into two variants, i.e., severe salt
wasting and simple virilizing groups, with the nonclassic
CAH, it was found that the prevalence of homosexuality and
bisexuality is proportional to the level of prenatal androgeniza-
tion. In addition, the level of prenatal androgenization was
moderately correlated to the masculinization of nonsexual
behavior (Meyer-Bahlburg et al., 2007). There seem to be no
significant differences, however, in playing behavior or sexual
orientation between men with CAH and their healthy relatives
(Hines et al., 2004).
Prenatal exposure to amphetamine-based drugs or thyroid
hormones increases the chances of female homosexuality (Ellis
and Hellberg, 2005). A recent study found a relationship
between thyroid dysfunction and homosexuality in both
male and female, but the sample was relatively small and the
percentage of homosexuality in the sample population was
2%, lower than in the general population (Sabuncuoglu,
2015).
In rodents, maternal stress demasculinizes and feminizes
sexual behavior by apparently delaying the surge of testos-
terone needed for sexual differentiation of the brain. Maternal
stress has been associated with male homosexuality in humans,
but the studies have been inconclusive (Bailey et al., 1991; Ellis
and Cole-Harding, 2001). Alcohol reduces circulating levels of
testosterone in adult and neonatal rats. Also, male offspring of
rats exposed to alcohol during pregnancy display feminized
sexual behavior. Nicotine has also been associated with femi-
nizing sexual behavior in male rodents. However, a relation
between alcohol consumption during pregnancy and homo-
sexuality, either male or female, has yet to be shown. One study
did find a relationship between nicotine consumption during
pregnancy and female homosexuality in offspring, which was
increased when associated with stress (Ellis and Cole-
Harding, 2001), probably due to higher levels of circulating
testosterone during pregnancy of both mother and offspring
(Kandel and Udry, 1999; Smith et al., 2003).
Since circulating testosterone levels during pregnancy over-
lap between XX and XY fetuses (see above), there is lack of
information explaining the familial expression of homosexu-
ality based upon testosterone level changes. Rice et al. (2012)
presented a homosexuality model based on ‘epigenetic canali-
zation’ of sexual development. He proposes that there is a sexu-
ally dimorphic sensitivity to circulating androgens, with XY
fetuses having a higher sensitivity compared to XX fetuses.
The different sensitivities are canalized by epigenetic marks
established during early development, and they are present
both in the germ line and somatic cells and can therefore be
heritable. Although many of these marks are erased, others,
i.e., imprinted genes, are not (Hemberger et al., 2009), and
following this erasure, there is an almost complete de novo
epi-marking silencing or activating gene expression
(Hemberger et al., 2009). By the stem cell stage of the blasto-
cyst, XX embryos are epigenetically different from XY embryos
(Rice et al., 2012). Epigenetic marks, which at this point, favor,
for example, mechanisms that protect XX fetuses from high
testosterone levels, or XY fetuses from low testosterone levels,
would be evolutionary adaptive. However, if these epi-marks
are highly heritable and not erased in offspring of the opposite
sex, they could contribute to gonad-trait discordances, and thus
are sexually antagonistic (Rice et al., 2012).
5.12.3.2.2 Postmortem Studies
Structural brain differences have been described in relation to
sexual orientation. The suprachiasmatic nucleus (SCN) of the
hypothalamus, the biological clock, is 1.7 times bigger and
has 2.1 times as many cells in homosexual males compared
to the control group of males (Swaab and Hofman, 1990;
Swaab, 2008). LeVay (1991) reported that homosexual men
and heterosexual women have a smaller volume of INAH-3
when compared to heterosexual men. The anterior commissure
(AC) was also found to be bigger in homosexual men when
compared to heterosexual women (18% bigger) and hetero-
sexual men (34%) (Allen and Gorski, 1992). The AC is a tract

that is in charge of the connection between the left and right
temporal cortex. Since it is larger in heterosexual women than
in heterosexual men, it may be involved in sex differences in
relation to cognition, language, and cerebral lateralization
(Allen and Gorski, 1992; Swaab, 2008).
5.12.3.2.3 Positron Emission Tomography and MRI Studies
An MRI study showed that the perirhinal cortex of homo-
sexual female participants had a masculinized GM pattern
without significant differences between homosexual and
heterosexual men (Ponseti et al., 2007). A study by Savic
and Lindström showed asymmetry in hemisphere volumes
in male heterosexuals and homosexual females, with a larger
right hemisphere in the homosexual females. Combining
positron emission tomography (PET) and MRI scans, they
found a possible relationship between these asymmetries
and connections, with homosexual subjects (both male and
female) having sex-atypical hemispheric ratios and patterns
of amygdala connectivity (Savic and Lindström, 2008). In
another PET study, it was found that the hypothalamus of
homosexual men appeared to be less responsive to fluoxetine
than that of heterosexual men, indicating different activities
in the serotonergic system (Kinnunen et al., 2004). In PET
studies investigating hypothalamic responses to smelling
putative pheromones, it was found that the response of
homosexual men to these smells was similar to that of hetero-
sexual women but different from that of heterosexual men
(Savic et al., 2005) while the response of homosexual women
was similar to that of heterosexual men but different from that
of heterosexual women (Berglund et al., 2006). In resting
state, the functional connectivity between the left inferior
occipital gyrus (which has a role in visuospatial processing)
and the right cuneus was reduced in homosexual men
compared to heterosexual men. In addition, the regional
homogeneity in the left inferior occipital gyrus and the func-
tional connectivity in the right thalamus and cuneus had posi-
tive correlations to Kinsey scores (Hu et al., 2013).
Homosexual men differ from heterosexual men in brain acti-
vation areas during visually evoked sexual arousal (Hu et al.,
2008). Homosexual men and heterosexual women have
thinner cortices in visual areas and smaller thalamus volumes
than heterosexual men. Heterosexual women and homo-
sexual men do not differ in these areas (Abé et al., 2014).
These data not only illustrate structural differences, but they
also suggest brain functional differences also occur that is
dependent upon sexual orientation.
5.12.3.3 Pedophilia
Pedophilia is defined as an adult’s sexual attraction to prepu-
bescent children and seems to have different arousal patterns
from hebephilia, which is the sexual response to pubescent
children (Seto, 2009). The DSM V differentiates pedophilia
from pedophilic disorder, where the sexual urges or fantasies
toward prepubescent children cause marked distress, interper-
sonal difficulty or the individual has acted on these urges.
Therefore, pedophilia, the mere attraction or sexual predilec-
tion for prepubescent children is not considered pathology
(Mohnke et al., 2014; Tenbergen et al., 2015). It is a sexual
preference different from sexual offenders against children
Sexual Identity and Sexual Orientation 287
(Tenbergen et al., 2015). Clinically this is an important distinc-
tion, because a high percentage of pedophiles do not act on
their sexual urges, and 40–50% of sex offenders, that have
engaged in sexual contact with children and are also called
pedosexuals, have equal or higher sexual arousal with adults
(Seto, 2009). It is a predominantly male condition – although
there are women who are pedophiles – with a prevalence esti-
mated to be around 3% (Mohnke et al., 2014). Pedophilia is
considered to be an unchangeable orientation.
A series of case reports involving brain tumors, dementia,
Parkinson’s, and other neurological diseases (reviewed in
Mohnke et al.,2014) have shown that these conditions can in
rare cases provoke pedophilic behavior. Other studies in child
sexual offenders have reported, in exceptional cases, changes of
sexual preference and reduced reoffending in child sexual
offenders (Marshal, 2008), although it is not clear if it is
a change in sexual preference or if it is just a matter of urge
control.
The etiology of pedophilia remains unknown, many
factors are considered to play a role. The fact that most studies
on pedophilia do not make a distinction between sex
offenders and pedophiliacs makes the little data available
difficult to evaluate. There is a constant finding that child
sexual offenders who had been sexually abused themselves
abuse younger children and have more indicators of pedo-
philic interest (Nunes et al., 2013). It is, however, not so clear
in pedophiles that do not engage in sexual contact with chil-
dren, and only a small percentage of sexually abused children
become or are pedophilic (Mohnke et al., 2014). A recent
study using an extended familial design for genetic behavioral
modeling found genetic evidence for pedophilia, but the non-
shared environmental effect in this study was greater (Alanko
et al., 2013). The possibility of neurodevelopmental perturba-
tions in pedophiles has gained interest lately. Neuropsycho-
logical deficits such as impaired response inhibition, slower
processing speed, diminished cognitive reasoning abilities,
as well as higher incidence of head trauma prior to the age
of 13 have been observed in pedophilic sex offenders (pedo-
sexuals) (Mohnke et al., 2014).
Structural MRI studies have shown variable findings in rela-
tion to pedophiles. Three studies found diminished amygdala
volumes in pedophiles, which could indicate alterations in
the processing of sexual arousal (Mohnke et al., 2014). One
group found only WM reductions (Cantor and Blanchard,
2012). Functional studies on pedophiles have not been able
to present consistency in findings, making it difficult to draw
a conclusion (Mohnke et al., 2014; Kärgel et al., 2015). A recent
study with a more complete analysis and methodology evalu-
ated the functional connectivity at rest between pedosexuals
(sex offenders), pedophiles without history of committing
sexual abuse, and controls, in two networks, i.e., the default
mode network and the limbic network. Diminished functional
connectivity in both networks was found in the child sexual
offender group compared to the other two groups, with
reduced connectivity between the left amygdala and the orbito-
frontal as well as the anterior prefrontal regions. Their findings
suggest that the alterations in these networks, which are
involved in cognitive, motivational, and emotional functions
during the processing of sexual incentives, are related more to
child sexual abuse than to pedophilia (Kärgel et al., 2015).
288 Sexual Identity and Sexual Orientation
Since most studies on pedophilia do not make a distinction
between sex offenders and pedophiliacs, there are very little
data on etiology.
5.12.4 Conclusions
Up to the 1980s, it was thought that a child’s behavior was
made male or female by postnatal social influences. This flawed
concept has led to the immediate operations of newborns with
indeterminate sex organs in the 1960s and 1970s and has
ruined many lives, since the possibility of an intrauterine sexual
differentiation of the brain was not taken into account.
The presence or absence of testosterone causes the fetus to
develop male or female sex organs between the 6th and 12th
week of pregnancy. The brain differentiates along male or
female lines in the second half of pregnancy. It is in that period
that our gender identity – the feeling of being a man or
a woman – and our sexual orientation – heterosexual, homo-
sexual, or bisexual – is programmed into the hardware of our
brains for the rest of our lives. This process of sexual differenti-
ation of the brain is for the major part caused by a surge of
testosterone in boys in the second half of pregnancy and the
absence of such a peak in sex hormones in girls. In addition,
sexual differentiation of the brain is influenced by genetic poly-
morphisms, epigenetic factors even before the testes begin to
produce testosterone, and can be disturbed by drugs and chem-
icals in the environment. The result of all these factors involved
in brain development in general, and in sexual differentiation
of the brain in particular, is a great variability in all aspects of
gender identity and sexual orientation. There is no evidence
that postnatal social factors play an essential role in the devel-
opment of gender identity or sexual orientation.
Acknowledgments
We want to thank Wilma Verweij for her secretarial assistance.
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