Transendokrinologiaa

2007 kirjoitti:

DOI: 10.1530/eje.1.02248
European Journal of Endocrinology, Vol 155, Issue suppl_1, 107-114
Copyright © 2006 by Society of the European Journal of Endocrinology

ARTICLE


Changing your sex changes your brain: influences of testosterone and
estrogen on adult human brain structure


Hilleke E Hulshoff Pol, Peggy T Cohen-Kettenis1, Neeltje E M Van Haren,
Jiska S Peper, Rachel G H Brans, Wiepke Cahn, Hugo G Schnack, Louis J G
Gooren2 and René S Kahn


Department of Psychiatry, Rudolf Magnus Institute of Neuroscience,
University Medical Center Utrecht, A01.126, Heidelberglaan 100, 3584 CX
Utrecht, The Netherlands, 1 Department of Medical Psychology and 2
Department of Endocrinology, VU University Medical Center, Amsterdam,
The Netherlands


(Correspondence should be addressed to H E Hulshoff Pol; Email:
[email protected])


Abstract


Objective: Sex hormones are not only involved in the formation of
reproductive organs, but also induce sexually-dimorphic brain
development and organization. Cross-sex hormone administration to
transsexuals provides a unique possibility to study the effects of sex
steroids on brain morphology in young adulthood.


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


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


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


Introduction
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
production 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 hypothalamus 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 hormones in adulthood are required for the
maintenance 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, reflecting (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.


Methods


Subjects
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 explanation 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.


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Table 1 Demographics and brain volumes (mean (S.D.); ml) in
transsexuals and comparisons subjects.


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) = 4.6 ms, repetition
time (TR) = 30 ms, flip angle = 30°, field of view (FOV) = 256 x 256
mm2) with 160-180 contiguous coronal 1.2 mm slices and a T2-weighted
dual echo-turbo spin echo (TE1 = 14 ms, TE2 = 80 ms, TR = 6350 ms,
flip angle = 90°, FOV = 256 x 256 mm2) 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
(TE1 = 9 ms, TE2 = 100 ms, flip angle = 90°, FOV = 250 x 250 mm2) with
17 axial 5 mm slices and 1.2 mm gap of the whole head was acquired for
clinical neurodiagnostic evaluation.


Image processing
Processing was done on Hewlett Packard UNIX 9000 workstations and
conventional Linux Personal Computers. All images were coded to ensure
blindness for subject identification and diagnosis; scans were put into
Talairach frame (no scaling) and corrected for inhomogeneities 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.


Statistical analysis
Data were examined for outliers, extreme values, and normality of
distribution. There was no need for transformations. To investigate
differences and changes 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 (transsexuals, 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.


Results
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 x 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 x 50 µg/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 hypogonadal 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 transsexuals; thus, group-by-time
interaction effects for the influence of testosterone and estrogen were
considered relatively conservative.


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Figure 1 Magnetic resonance image acquisition of the whole-head
coronal slice. Segmentation of the hypothalamus is shown in white.


General linear modeling for repeated measures, correcting for age and
intracranial volume, revealed significant group (transsexuals,
comparisons) x sex (male, MF, female, FM) x time (scan 2 minus scan 1)
interactions for whole brain (F(1,23) = 9.26, P = 0.006) and
hypothalamus (F(1,23) = 5.36, P = 0.03) volumes (Table 1, Fig. 2). The
significant group x sex x time effects were due to a decrease in
hypothalamus and total brain volume in MFs treated with anti-androgens
estrogens (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.


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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.


Moreover, testosterone administration to FMs increased total brain
volume, whereas it remained unchanged in female comparison subjects.
Significant group x sex x time interactions were also found for third
(F(1,23) = 16.56, P < 0.0001) and lateral (F(1,23) = 21.90, 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) = 5.67, P = 0.036). 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 transsexualism (F(1,24) = 10.10, P = 0.004). 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 significance. Third ventricle volume was larger in
the transsexuals than in the controls, although not significant (main
effect for group: F(1,23) = 3.36, P = 0.08; 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 results.


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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).


Discussion
The findings suggest that treatment of MFs with estrogens and
anti-androgens decreases the male brain size towards female
proportions, whereas treatment 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 transsexuals 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 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 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 hormones.


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 testosterone 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 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 hormones.


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. Moreover, 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-androgen estrogen 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 hormones.


Acknowledgements


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
manuscript.


Footnotes
This paper was presented at the 4th Ferring Pharmaceuticals
International Paediatric Endocrinology Symposium, Paris (2006). Ferring
Pharmaceuticals has supported the publication of these proceedings.


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