Changing your sex changes your brain: inﬂuences of
testosterone and estrogen on adult human brain structure
Hilleke E Hulshoff Pol, Peggy T Cohen-Kettenis
, Neeltje E M Van Haren, Jiska S Peper, Rachel G H Brans,
Wiepke Cahn, Hugo G Schnack, Louis J G Gooren
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, A01.126, Heidelberglaan 100, 3584 CX Utrecht,
Department of Medical Psychology and
Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands
(Correspondence should be addressed to H E Hulshoff Pol; Email: firstname.lastname@example.org)
Objective: Sex hormones are not only involved in the formation of reproductive organs, but also induce
sexually-dimorphic brain development and organization. Cross-sex hormone administration to
transsexuals provides a unique possibility to study the effects of sex steroids on brain morphology in
Methods: Magnetic resonance brain images were made prior to, and during, cross-sex hormone
treatment to study the inﬂuence of anti-androgenCestrogen treatment on brain morphology in eight
young adult male-to-female transsexual human subjects and of androgen treatment in six female-
Results: Compared with controls, anti-androgenCestrogen treatment decreased brain volumes of
male-to-female subjects towards female proportions, while androgen treatment in female-to-male
subjects increased total brain and hypothalamus volumes towards male proportions.
Conclusions: The ﬁndings suggest that, throughout life, gonadal hormones remain essential for
maintaining aspects of sex-speciﬁc differences in the human brain.
European Journal of Endocrinology 155 S107–S114
Transsexualism is the condition in which a person with
apparently normal somatic sexual differentiation of one
sex is convinced that he or she is actually a member of the
opposite sex. This sense is so pronounced and persistent
that transsexuals seek treatment to, as far as medically
possible, physically change their bodies from male into
female or vice versa. Prior to surgical sex reassignment,
transsexuals receive treatment with cross-sex hormones.
Male-to-female transsexuals (MFs) are treated with
estrogens and anti-androgens (to suppress the pro-
duction and biological effects of circulating androgens)
and female-to-male transsexuals (FMs) are treated with
androgens (in FMs, androgens, without additional
hormone treatment, usually suppress menstruation;
circulating estrogens are not substantially reduced as a
result of peripheral aromatization of administered
androgens). There is no known fundamental difference
in sensitivity to the biological action of sex steroids on the
basis of genetic conﬁgurations or gonadal status. Thus,
in transsexuals, the inﬂuence of cross-sex hormones can
be studied relatively independent of their original
endocrine status as male or female.
It is well established in mammals that differences in
male and female brain structures can be reversed by sex
hormones, even in adulthood (1). However, it is not
known whether alterations in sex hormone levels can
change structures of the human brain in adulthood. In
human adults, the volumes of the brain and hypo-
thalamus of males tend to be larger than those of females
(2). The preoptic nucleus of the hypothalamus is even
twice as large in males as in females (3). Moreover, in
some studies, when comparing the fractions of gray and
white matter in the brain, adult females as compared
with males were found to have a higher fraction of gray
matter, whereas adult males as compared with females
had a higher fraction of white matter (4, 5).
In rodents, brain differences between the sexes
supposedly reﬂect differential exposure to sex hormones
during perinatal brain development (6). Typically,
perinatal exposure to high levels of testosterone results
in male brain structure and in the absence of androgen
exposure, female brain structure develops. In humans,
testosterone probably exerts its masculinizing inﬂuence
on the brain during prenatal development (7). However,
we hypothesize that, in addition, circulating sex
This paper was presented at the 4th Ferring Pharmaceuticals
International Paediatric Endocrinology Symposium, Paris (2006).
Ferring Pharmaceuticals has supported the publication of these
European Journal of Endocrinology (2006) 155 S107–S114 ISSN 0804-4643
q2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02248
Online version via www.eje-online.org
hormones in adulthood are required for the mainten-
ance of sex differences in the human brain.
A few studies on brain structure in transsexuals have
been conducted in post-mortem tissue. The bed nucleus
of the stria terminalis of the hypothalamus, larger in
males than in females, was found to be of female size in
six MFs (8, 9) and of male size in one FM (9). All these
transsexuals had received cross-sex hormone treatment
before their brains were studied. Therefore, the altered
size of the bed nucleus of the stria terminalis could have
been due to the exposure of cross-sex hormones in adult
life. Alternatively, the different size of the bed nucleus of
the stria terminalis in transsexuals could have been
present prior to cross-sex hormones treatment, reﬂect-
ing (potentially hormonally determined) differences in
the development of the (pre- and perinatal) brain, or
possibly genetic differences, between transsexuals and
non-transsexuals (10). The aim of our study was to
examine the inﬂuence of exposure to high levels of
cross-sex hormones on brain structures in adulthood.
Eight MFs and six FMs were recruited through the
Outpatient Clinic from the Department of Psychiatry,
University Medical Center Utrecht, The Netherlands, and
through the Department of Endocrinology, VU University
Medical Center, Amsterdam, The Netherlands, and
compared with nine male and six female healthy
comparison subjects (Table 1). Subjects signed informed
consent after full explanation of the study. Inclusion
criteria for transsexual patients were DSM-IV criteria for
gender identity disorder, referral for hormone treatment,
no severe medical illness, and age between 16 and 50
years. The diagnosis of gender identity disorder was made
according to the structured clinical interview for DSM-IV
axis-I disorders (11). Patients participated in the study
after it was decided that they were eligible for hormone
treatment. This decision was made according to the
clinical protocols for the diagnosis and treatment of
transsexuals of the University Medical Center Utrecht and
VU University Medical Center, Amsterdam (12). Healthy
comparison subjects were included from the structural
neuroimaging database at the Department of Psychiatry,
University Medical Center, Utrecht; following full expla-
nation of all procedures, subjects signed informed consent.
The healthy comparison subjects were matched to the
transsexuals for age and original sex at ﬁrst measurement.
In addition, years of education – deﬁned as the total
number of years of education that was successfully
completed – and scan interval between the ﬁrst and the
second magnetic resonance imaging scan acquisition in
days was measured in each group. The Medical Ethical
Committee for Human Subjects at the University Medical
Center Utrecht approved the study.
Brain image acquisition
Magnetic resonance T1- and T2-weighted images were
acquired on a Philips NT scanner operating at 1.5 T in
all subjects. A three-dimensional-fast ﬁeld echo (echo
time (TE)Z4.6 ms, repetition time (TR)Z30 ms, ﬂip
angleZ308, ﬁeld of view (FOV)Z256!256 mm
160–180 contiguous coronal 1.2 mm slices and a T2-
weighted dual echo–turbo spin echo (TE1Z14 ms,
TE2Z80 ms, TRZ6350 ms, ﬂip angleZ908,FOVZ
) with 120 contiguous coronal 1.6 mm
slices of the whole head were used for the quantitative
measurements. In addition, a T2-weighted dual echo–
turbo spin echo (TE1Z9 ms, TE2Z100 ms, ﬂip angleZ
) with 17 axial 5 mm slices
and 1.2 mm gap of the whole head was acquired for
clinical neurodiagnostic evaluation.
Processing was done on Hewlett Packard UNIX 9000
workstations and conventional Linux Personal Compu-
ters. All images were coded to ensure blindness for
subject identiﬁcation and diagnosis; scans were put into
Talairach frame (no scaling) and corrected for inhomo-
geneities in the magnetic ﬁeld. Quantitative assessments
of the intracranial, total brain, gray and white matter of
the cerebrum (total brain excluding cerebellum and
stem), lateral and third ventricles, and peripheral
cerebrospinal ﬂuid (CSF) volumes were performed
based on the histogram analyses and a series of
mathematical morphology operators to connect all
voxels of interest, as implemented and validated
previously (13, 14; www.smri.nl). The interrater
reliability of the automated volume measurements
determined by the intraclass correlation coefﬁcient in
ten brains was 0.95 and higher.
Hypothalamus segmentation was done in coronal
slices according to Nieuwenhuys et al. (15). The anterior
boundary was the ﬁrst coronal slice posterior of the
anterior commissure (AC), where the AC is no longer
continuous and does not run through the emerging
hypothalamus. Posterior, the last slice is where the
mamillary bodies (excluded) end in the mid-sagittal slices
– sagittal section is where the mamillary bodies are
completed. Inferior, the hypothalamus ends where optic
chiasma, infundibulum, and mamillary bodies begin.
Superior, the AC–PC plane was used, which itself was not
included in the hypothalamus. Lateral, the segmentation
was limited by white matter. The intrarater reliability
determined by the intraclass correlation coefﬁcient in ten
brains was 0.86.
Data were examined for outliers, extreme values, and
normality of distribution. There was no need for
transformations. To investigate differences and changes
S108 H E Hulshoff Pol and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
over time in brain volumes between groups, multiple
general linear modeling for repeated measures analyses
were done for each of the volume measures (i.e. whole
brain, hypothalamus, cerebral gray and white matter,
and lateral and third ventricles), with group (transsex-
uals, comparisons), sex (male, MF, female, FM) as
between-subject factors, and time (scan 2 minus
scan 1) as within-subject factors. Age and intracranial
volume at ﬁrst measurement were added as covariates.
In case of a signiﬁcant ﬁnding, years of education and
scan interval were also added to the statistical analysis
as covariates to assess their possible inﬂuence.
The inﬂuence of sex hormone treatment on brain
morphology in young adult humans between 16 and
45 years of age (on average 25 years) was measured in
eight MF and six FM human subjects (Table 1). High-
resolution magnetic resonance brain images were
obtained prior to and during cross-sex hormone
treatment after a 4-month interval and prior to sex
reassignment surgery (Fig. 1). MFs received dual
therapy: the anti-androgen cyproterone acetate
(Androcur) (2!50 mg/day), having anti-androgenic
properties both by its progestational action and
competing for the androgen receptor, and a synthetic
oral estrogen ethinylestradiol (2!50 mg/day). The
estrogen doses used are 2–3 times more biopotent
than traditional estrogen replacement in women. FMs
received parenteral testosterone esters (250 mg/2
weeks i.m.). The testosterone doses were comparable
to those used for testosterone replacement in hypogo-
nadal males. Intracranial, whole brain, gray and white
matter of the cerebrum, hypothalamus, and lateral and
third ventricle volume changes in the transsexuals were
compared with brain volume changes in nine male and
six female healthy comparison subjects over a 1-year
interval. The comparison subjects were matched with
the transsexuals for age and original sex at ﬁrst
measurement. Years of education and scan interval
differed between transsexuals and comparisons; in case
of a signiﬁcant ﬁnding, they were added to the
statistical analysis as covariates. Note that the scan
interval was longer in comparisons than in transsex-
uals; thus, group-by-time interaction effects for the
inﬂuence of testosterone and estrogen were considered
General linear modeling for repeated measures,
correcting for age and intracranial volume, revealed
signiﬁcant group (transsexuals, comparisons)!sex
(male, MF, female, FM)!time (scan 2 minus scan 1)
interactions for whole brain (F(1,23)Z9.26, PZ0.006)
and hypothalamus (F(1,23)Z5.36, PZ0.03) volumes
(Table 1, Fig. 2). The signiﬁcant group!sex!time effects
were due to a decrease in hypothalamus and total brain
volume in MFs treated with anti-androgensCestrogens
Table 1 Demographics and brain volumes (mean (S.D.); ml) in transsexuals and comparisons subjects.
Intracranium Total brain Hypothalamus Third ventricle Lateral ventricle Gray matter White matter
(n)Scan 1 Scan 2 Scan 1 Scan 2 Scan 1 Scan 2 Scan 1 Scan 2 Scan 1 Scan 2 Scan 1 Scan 2 Scan 1 Scan 2
MF (8) 25 10 128 1521 1523 1338 1307 1.07 1.01 0.95 1.18 14 17 710 694 462 450
(9) (3) (24) (107) (114) (98) (106) (0.13) (0.12) (0.40) (0.48) (8) (8) (52) (64) (59) (47)
FM (6) 28 13 148 1416 1414 1226 1238 0.93 0.93 0.87 0.72 14 13 364 344 443 444
(8) (2) (54) (149) (150) (128) (125) (0.15) (0.19) (0.28) (0.28) (7) (6) (69) (82) (49) (52)
M (9) 25 13 393 1614 1619 1413 1422 1.05 1.07 0.73 0.70 14 13 634 644 443 444
(8) (4) (45) (161) (160) (132) (123) (0.18) (0.17) (0.24) (0.29) (17) (18) (52) (48) (80) (73)
F (6) 23 14 358 1406 1409 1248 1253 1.00 0.95 0.55 0.55 11 11 652 659 439 435
(6) (3) (24) (69) (75) (83) (92) (0.05) (0.07) (0.37) (0.33) (5) (5) (57) (58) (32) (27)
MF, male-to-female transsexuals; FM, female-to-male transsexuals; M, male controls; F, female controls.
Inﬂuences of testosterone and estrogen on adult human brain structure S109EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
(suppressing testosterone virtually totally) after a
4-month interval compared with male comparison
subjects, who showed a small increase. In addition,
these effects were due to a lack of change in hypothalamic
volume in testosterone-treated FMs after a 4-month
interval, whereas it decreased in female comparison
subjects. Moreover, testosterone administration to FMs
increased total brain volume, whereas it remained
unchanged in female comparison subjects.
Moreover, testosterone administration to FMs increased
total brain volume, whereas it remained unchanged in
female comparison subjects. Signiﬁcant group!sex!
time interactions were also found for third (F(1,23)Z
16.56, P!0.0001) and lateral (F(1,23)Z21.90, P!
0.0001) ventricle volumes. The effects were due to
increases in ventricle volumes in MFs as compared with
a lack of change in third ventricle volume and subtle
increase in lateral ventricle volume in male comparison
subjects. Moreover, the ﬁndings were due to decreases in
third and lateral ventricle volumes in FMs as compared
with no change or subtle increases in volume in female
comparison subjects. No signiﬁcant effects were found for
overall cerebral gray and white matter volumes.
In the young adult control subjects, no signiﬁcant
changes in volumes over time were found, except for an
increase in lateral ventricle volume irrespective of sex
(F(1,11)Z5.67, PZ0.036). Intracranial volume
showed a small (and insigniﬁcant) increase in volume
of 0.2%. Although not signiﬁcant, hypothalamus
volume in female controls decreased over time.
As expected, at ﬁrst measurement, intracranial
volume was signiﬁcantly larger in males as compared
with females irrespective of the condition of transsexu-
alism (F(1,24)Z10.10, PZ0.004). No differences in
intracranial volume were found between transsexuals
and comparisons. After controlling for intracranial
volume at initial measurement, no signiﬁcant
differences between the sexes or between transsexuals
and control subjects were found for any of the brain
volume measures. The relative proportion of white
matter to gray matter was somewhat larger in the
control females and the relative proportion of gray
matter was somewhat larger in the control males,
whereas the opposite was found for the transsexuals.
However, this ﬁnding did not reach statistical signi-
ﬁcance. Third ventricle volume was larger in the
transsexuals than in the controls, although not
signiﬁcant (main effect for group: F(1,23)Z3.36,
PZ0.08; Table 1, Fig. 3). Thus, it is unlikely that the
sexual dimorphic effects of sex hormone treatment on
brain volumes over time were due to initial differences
between groups or sexes. Moreover, it is also unlikely
that level of education or scan interval inﬂuenced the
results. Adding these factors to the analyses did not alter
The ﬁndings suggest that treatment of MFs with
estrogens and anti-androgens decreases the male
brain size towards female proportions, whereas treat-
ment of FMs with androgens (not substantially affecting
circulating estrogen levels) increases the female brain
size towards male proportions. The magnitude of this
change (i.e. 31 ml over a 4-month period) is striking,
since it signiﬁes a decrease in brain volume, which is at
least ten times the average decrease of around 2.5 ml
per year in healthy adults (16). Moreover, please note
that consistent with the ﬁndings in the young adult
control subjects of the present study, the longitudinal
brain volume changes in young adults are normally
small as compared with the older adults (17). The
changes in total brain and hypothalamus volumes
following cross-sex hormone treatment in the transsex-
uals were mirrored by changes in their third and lateral
ventricle volumes, i.e. treatment with estrogens and
anti-androgens in MFs increased third and lateral
ventricle volumes, whereas treatment with androgens
decreased the third and lateral ventricle volumes in
FMs. This suggests that the total brain volume changes
are at least in part due to changes in medial brain
Figure 1 Magnetic resonance image
acquisition of the whole-head coronal slice.
Segmentation of the hypothalamus is
shown in white.
S110 H E Hulshoff Pol and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
structures surrounding these ventricles (including, but
not limited to, the hypothalamus, which lies in close
proximity to the third ventricle). Considering that the
effects were not speciﬁc for gray (neurons, glia) or white
(myelinated axonal ﬁbers) matter suggests that both
alterations in nerve cells as well as in axonal ﬁbers may
be implicated in the anatomical brain changes following
cross-sex hormone treatment in humans. It is not
surprising that the inﬂuences of sex hormones on the
brain were not limited to the hypothalamus, but were
also expressed as changes in total brain size. Estrogen
and androgen receptor mRNA containing neurons are
not limited to the hypothalamus, but are distributed
throughout the adult human brain (18).
Prior to cross-sex hormone treatment, no differences
in brain volumes between transsexuals and comparison
subjects were found. Transsexuals had brain volumes in
agreement with their sex at birth. The intracranial
volume (and hence overall brain size) and the
hypothalamus volume of males were larger than the
females, irrespective of the condition of transsexualism.
This supports the notion that brain volume changes in
Figure 2 Brain volume changes in male-to-female and female-to-male transsexuals. Changes in hypothalamus, total brain, third and
lateral ventricle volumes in milliliters (mean change from 0 at ﬁrst measurement in bars, 95% conﬁdence interval in error bars, individual values
in circles) in transsexuals following cross-sex hormone treatment as compared with age- and sex-matched healthy comparison subjects.
Inﬂuences of testosterone and estrogen on adult human brain structure S111EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
transsexuals are related to cross-sex hormone treatment
and do not reﬂect pre-existent differences in brain
volume between transsexuals and comparisons
originating from earlier (pre- or perinatal) brain
development. Thus, our ﬁndings imply plasticity of
adult human brain structure to develop towards the size
of the opposite sex under the inﬂuence of cross-sex
Our ﬁndings of plastic changes in the total brain
volume and hypothalamus volume of transsexuals after
cross-sex hormone treatment are corroborated by the
observation of (in vitro) structural and functional brain
changes in animals upon hormonal manipulations.
Since the ﬁrst study on the reversal of natural sex
differences in neuronal connectivity following testoster-
one hormone treatment in the developing rat (19),
numerous studies have documented the inﬂuence of sex
hormones on brain structure. These include volumetric
studies on the inﬂuence of cross-sex hormone treatment
in adult animals. In the medial preoptic nucleus of the
Figure 3 Brain volumes in male-to-female and female-to-male transsexuals just prior to treatment. Hypothalamus, total brain, third and
lateral ventricle volumes at scan 1 in milliliters (mean volumes in bars, 95% conﬁdence interval in error bars, individual values in circles)
in transsexuals as compared with age- and sex-matched healthy comparison subjects (individual value of one control male’s lateral
ventricle (62 ml) not printed).
S112 H E Hulshoff Pol and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
hypothalamus (20) of adult gonadectomized male rats,
cross-sex hormone treatment (consisting of combined
estrogen/progesterone treatment) resulted in signiﬁcant
volume decreases towards female proportions. In
addition, in the adult female canary, testosterone
triggered the growth of brain vocal control nuclei
towards male proportions (21). Moreover, adult
castration of male rats and androgen treatment in
adult female rats resulted in the reversal of the sexual
dimorphism in the medial amygdala (22). Thus, the
brain volume changes towards the proportions of the
opposite sex observed in the transsexuals following
treatment with cross-sex hormones are in agreement
with studies in adult animals treated with cross-sex
Interestingly, in adult female canaries, testosterone
treatment also resulted in singing behavior normally
heard only from male canaries (23, 24). This implies
that the sex hormone-induced plastic changes in brain
anatomy may be functionally relevant. Indeed, in
transsexuals, cross-sex hormone treatment induces
changes in behavior and cognitive performance on
tests that are known to manifest differences between
males and females. In MFs, 3 months of estrogen
addition and testosterone suppression resulted in a
decline in anger and aggression proneness, sexual
arousal, sexual desire, and spatial ability (usually
males outperform females) and in an increase in verbal
ﬂuency (usually females outperform males) (24, 26,
27). In FMs, 3 months of testosterone treatment was
associated with an increase in aggression proneness,
sexual arousal, and spatial ability performance, whereas
it had a deteriorating effect on verbal ﬂuency tasks
(25, 28). These behavioral and cognitive ﬁndings in
transsexuals following cross-sex hormone treatment are
in line with the studies reporting inﬂuences of
endogenous and exogenous sex hormones on behavior
and cognition, as well as on cortical brain activation, in
non-transsexual adult humans (29, 30). Whether
functional brain changes accompany the anatomical
brain changes in transsexuals remains to be elucidated
using functional brain imaging techniques.
Biological mechanisms underlying the gonadal
hormone-related plasticity changes in young adult
human brains are not known. However, we know that
sex steroids have much in common with neurotropins.
For instance, like neurotropins, they regulate cell death.
Indeed, the most important mechanism by which
steroid hormones alter neuron number in sexually
dimorphic regions is by inﬂuencing cell death. In
addition, they are involved in neuronal migration,
neurogenesis, and neurotransmitter plasticity. More-
over, these hormones direct formation of sex-speciﬁc
neuronal networks by inﬂuencing axonal guidance and
synaptogenesis (1, 31). Testosterone treatment in the
adult female canary also induces newly activated and
expanded vasculature in the vocal control nucleus,
which substantially increases the production and
release of BDNF; BDNF is both spatially and temporally
associated with the recruitment of new neurons (32).
Functionally, sex hormones can alter neuronal
excitability in a sex-speciﬁc way (33). The changes in
excitability may be caused not only by altered electrical
properties of the membrane, but may also be caused by
alternations in neuronal morphology (34). Thus, our
reported volume changes in the brains of transsexuals
following cross-sex hormone treatment may represent
alterations in neuronal cell numbers or the number of
synapses. However, more work is needed to uncover
particular cells and speciﬁc genes on which testosterone
(and estrogen) act to regulate cell death in the central
nervous system (35).
In conclusion, our data show that in young adult
humans, androgen treatment increases the volume of
the female brain towards male proportions and anti-
androgenCestrogen treatment reduces the size of the
male brain towards female proportions. The ﬁndings
imply plasticity of adult human brain structure towards
the opposite sex under the inﬂuence of cross-sex
The authors thank the coordinator of the gender team J
Megens at the VU University Medical Center in
Amsterdam for his support with patient recruitment
and Dr E Fliers for comments on an earlier version of the
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Received 30 April 2006
Accepted 7 July 2006
S114 H E Hulshoff Pol and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155