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 Rene´ S Kahn |
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, A01.126, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands, 1Department of Medical Psychology and 2Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands |
(Correspondence should be addressed to H E Hulshoff Pol; Email: h.e.hulshoff@azu.nl) |
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-androgenCestrogen treatment on brain morphology in eight young adult male-to-female transsexual human subjects and of androgen treatment in six femaleto-male transsexuals. 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 |
Introduction in transsexuals, the influence of cross-sex hormones can |
be studied relatively independent of their original Transsexualism is the condition in which a person with endocrine status as male or female. apparently normal somatic sexual differentiation of one It is well established in mammals that differences in sex is convinced that he or she is actually a member of the male and female brain structures can be reversed by sex opposite sex. This sense is so pronounced and persistent hormones, even in adulthood (1). However, it is not that transsexuals seek treatment to, as far as medically known whether alterations in sex hormone levels can possible, physically change their bodies from male into change structures of the human brain in adulthood. In female or vice versa. Prior to surgical sex reassignment, human adults, the volumes of the brain and hypotranssexuals receive treatment with cross-sex hormones. thalamus of males tend to be larger than those of females Male-to-female transsexuals (MFs) are treated with (2). The preoptic nucleus of the hypothalamus is even estrogens and anti-androgens (to suppress the pro-twice as large in males as in females (3). Moreover, in |
duction and biological effects of circulating androgens) some studies, when comparing the fractions of gray and and female-to-male transsexuals (FMs) are treated with white matter in the brain, adult females as compared androgens (in FMs, androgens, without additional with males were found to have a higher fraction of gray hormone treatment, usually suppress menstruation; matter, whereas adult males as compared with females circulating estrogens are not substantially reduced as a had a higher fraction of white matter (4, 5). result of peripheral aromatization of administered In rodents, brain differences between the sexes androgens). There is no known fundamental difference supposedly reflect differential exposure to sex hormones in sensitivity to the biological action of sex steroids on the during perinatal brain development (6). Typically, basis of genetic configurations or gonadal status. Thus, 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, |
This paper was presented at the 4th Ferring Pharmaceuticals International Paediatric Endocrinology Symposium, Paris (2006). |
testosterone probably exerts its masculinizing influence Ferring Pharmaceuticals has supported the publication of these on the brain during prenatal development (7). However, proceedings. we hypothesize that, in addition, circulating sex
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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. |
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. |
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 mm2) with 160–180 contiguous coronal 1.2 mm slices and a T2weighted dual echo–turbo spin echo (TE1Z14 ms, TE2Z80 ms, TRZ6350 ms, flip angleZ908,FOVZ 256!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 (TE1Z9 ms, TE2Z100 ms, flip angleZ 908,FOVZ250!250 mm2) 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 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. |
Data were examined for outliers, extreme values, and normality of distribution. There was no need for transformations. To investigate differences and changes |
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