References 1.a: Brains of transsexuals resemble their target gender

The Role of Pubertal Hormones in the Development of Gender Identity: fMRI Studies

The present study is the first to demonstrate that sex differences in hypothalamic activation upon smelling the chemo-signal androstadienone are not acquired during sexual maturation, under the influence of gonadal hormones during puberty, but might be considered hard-wired responses, which already can be observed in prepubertal children. Moreover, the current study is the first to explore sex-atypical hypothalamic responses to androstadienone in male and female individuals with GD at two different developmental stages. Our results suggest that individuals with GD possess certain functional brain characteristics of their experienced gender and might have undergone atypical neuronal sexual differentiation, most likely during early brain development and not during puberty. Additional analyses in other functional (e.g., mental rotation, emotional face matching, resting state data) and structural (e.g., gray and white matter volumes or diffusion tensor imaging data) MRI measures, which are in preparation, should corroborate the present preliminary findings.

Author/-s:       Sarah M. Burke; J. Bakker

Publication:     Research and Perspectives in Endocrine Interactions, Brain Crosstalk in Puberty and Adolescence, 2015

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Hypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescents

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.

Author/-s:       Sarah M. Burke; Peggy T. Cohen-Kettenis; D. J. Veltman; D. T. Klink; J. Bakker

Publication:     Frontiers in Endocrinology, 2014

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More than Just Two Sexes: The Neural Correlates of Voice Gender Perception in Gender Dysphoria

Gender dysphoria (also known as “transsexualism”) is characterized as a discrepancy between anatomical sex and gender identity. Research points towards neurobiological influences. Due to the sexually dimorphic characteristics of the human voice, voice gender perception provides a biologically relevant function, e.g. in the context of mating selection. There is evidence for a better recognition of voices of the opposite sex and a differentiation of the sexes in its underlying functional cerebral correlates, namely the prefrontal and middle temporal areas. This fMRI study investigated the neural correlates of voice gender perception in 32 male-to-female gender dysphoric individuals (MtFs) compared to 20 non-gender dysphoric men and 19 non-gender dysphoric women. Participants indicated the sex of 240 voice stimuli modified in semitone steps in the direction to the other gender. Compared to men and women, MtFs showed differences in a neural network including the medial prefrontal gyrus, the insula, and the precuneus when responding to male vs. female voices. With increased voice morphing men recruited more prefrontal areas compared to women and MtFs, while MtFs revealed a pattern more similar to women. On a behavioral and neuronal level, our results support the feeling of MtFs reporting they cannot identify with their assigned sex.

Author/-s:       Jessica Junger; Ute Habel; Sabine Bröhr; Josef Neulen; Christiane Neuschaefer-Rube; Peter Birkholz; Christian Kohler; Frank Schneider; Birgit Derntl; Katharina Pauly

Publication:     PLOS One, 2014

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Alterations in serotonin transporter asymmetry in male-to-female transsexuals measured by brain pet

Introduction: The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, indicating similar asymmetries in associated neurotransmitter systems.

Objectives: To investigate a potential brain asymmetry of the serotonin transporter (SERT) distribution using Positron Emission Tomography (PET).

Aims: As brain asymmetries differ between sexes, we aimed to compare serotonin transporter asymmetry between females, males and male-to-female transsexuals whose brains are considered to be partly feminized.

Methods: 36 subjects aged 19-54 years (9 female controls, 13 male controls and 14 male-to-female transsexuals) were measured with PET and [11C]DASB. Whole-brain voxel-wise SERT binding potential (BPND) maps were computed using a tracer-specific symmetric template. Statistics comprised repeated measures ANOVA with group as the between subjects factor, voxel-wise SERT asymmetry as repeated factor and group asymmetry as interaction term.

Results: SERT binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus (p < 0.05 FDR-corrected). Further, male controls showed a rightward asymmetry in the midcingulate cortex (p > 0.05 FDR-corrected) which was absent in females and male-to-female transsexuals.

Conclusions: Our data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in male-to-female transsexuals may be attributed to an absence of brain masculinization in this region.

Author/-s:       G. S. Kranz; A. Hahn, D. Haeusler, C. Philippe, U. Kaufmann, W. Wadsak, M. Mitterhauser, S. Kasper, R. Lanzenberger

Publication:     European Psychiatry, 2013

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Brain Signature Characterizing the Body-Brain-Mind Axis of Transsexuals

Individuals with gender identity disorder (GID), who are commonly referred to as transsexuals (TXs), are afflicted by negative psychosocial stressors. Central to the psychological complex of TXs is the conviction of belonging to the opposite sex. Neuroanatomical and functional brain imaging studies have demonstrated that the GID is associated with brain alterations. In this study, we found that TXs identify, when viewing male-female couples in erotic or non-erotic (“neutral”) interactions, with the couple member of the desired gender in both situations. By means of functional magnetic resonance imaging, we found that the TXs, as opposed to controls (CONs), displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs.

Author/-s:       Hsiao-Lun Ku; Chia-Shu Lin; Hsiang-Tai Chao; Pei-Chi Tu; Cheng-Ta Li; Chou-Ming Cheng; Tung-Ping Su; Ying-Chiao Lee; Jen-Chuen Hsieh

Publication:     PLoS One, 2013

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Cortical Thickness in Untreated Transsexuals

Sex differences in cortical thickness (CTh) have been extensively investigated but as yet there are no reports on CTh in transsexuals. Our aim was to determine whether the CTh pattern in transsexuals before hormonal treatment follows their biological sex or their gender identity. We performed brain magnetic resonance imaging on 94 subjects: 24 untreated female-to-male transsexuals (FtMs), 18 untreated male-to-female transsexuals (MtFs), and 29 male and 23 female controls in a 3-T TIM-TRIO Siemens scanner. T1-weighted images were analyzed to obtain CTh and volumetric subcortical measurements with FreeSurfer software. CTh maps showed control females have thicker cortex than control males in the frontal and parietal regions. In contrast, males have greater right putamen volume. FtMs had a similar CTh to control females and greater CTh than males in the parietal and temporal cortices. FtMs had larger right putamen than females but did not differ from males. MtFs did not differ in CTh from female controls but had greater CTh than control males in the orbitofrontal, insular, and medial occipital regions. In conclusion, FtMs showed evidence of subcortical gray matter masculinization, while MtFs showed evidence of CTh feminization. In both types of transsexuals, the differences with respect to their biological sex are located in the right hemisphere.

Author/-s:       Leire Zubiaurre-Elorza; Carme Junque; Esther Gómez-Gil; Santiago Segovia; Beatriz Carrillo; Giuseppina Rametti; Antonio Guillamon

Publication:     Cerebral cortex, 2013

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Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls – A Voxel Based Morphometry Study

Gender identity disorder (GID) refers to transsexual individuals who feel that their assigned biological gender is incongruent with their gender identity and this cannot be explained by any physical intersex condition. There is growing scientific interest in the last decades in studying the neuroanatomy and brain functions of transsexual individuals to better understand both the neuroanatomical features of transsexualism and the background of gender identity. So far, results are inconclusive but in general, transsexualism has been associated with a distinct neuroanatomical pattern. Studies mainly focused on male to female (MTF) transsexuals and there is scarcity of data acquired on female to male (FTM) transsexuals. Thus, our aim was to analyze structural MRI data with voxel based morphometry (VBM) obtained from both FTM and MTF transsexuals (n = 17) and compare them to the data of 18 age matched healthy control subjects (both males and females). We found differences in the regional grey matter (GM) structure of transsexual compared with control subjects, independent from their biological gender, in the cerebellum, the left angular gyrus and in the left inferior parietal lobule. Additionally, our findings showed that in several brain areas, regarding their GM volume, transsexual subjects did not differ significantly from controls sharing their gender identity but were different from those sharing their biological gender (areas in the left and right precentral gyri, the left postcentral gyrus, the left posterior cingulate, precuneus and calcarinus, the right cuneus, the right fusiform, lingual, middle and inferior occipital, and inferior temporal gyri). These results support the notion that structural brain differences exist between transsexual and healthy control subjects and that majority of these structural differences are dependent on the biological gender.

Author/-s:       Lajos Simon; Lajos R. Kozák; Viktória Simon; Pál Czobor; Zsolt Unoka; Ádám Szabó; Gábor Csukly

Publication:     PLoS One, 2013

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Cerebral serotonin transporter asymmetry in females, males and male-to-female transsexuals measured by PET in vivo

The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, which indicates similar asymmetries in associated neurotransmitter systems. Here, our aim was to investigate a potential asymmetry of the serotonin transporter distribution using positron emission tomography and the radioligand [11C]DASB in vivo. As brain asymmetries may differ between sexes, we further aimed to compare serotonin transporter asymmetry between females, males and male-to-female (MtF) transsexuals whose brains are considered to be partly feminized. Voxel-wise analysis of serotonin transporter binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus. Further, male controls showed a rightward asymmetry in the midcingulate cortex, which was absent in females and MtF transsexuals. The present data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in MtF transsexuals may be attributed to an absence of brain masculinization in this region.

Author/-s:       Georg S. Kranz; Andreas Hahn; Pia Baldinger; Daniela Haeusler; Cecile Philippe; Ulrike Kaufmann; Wolfgang Wadsak; Markus Savli; Anna Hoeflich; Christoph Kraus; Thomas Vanicek; Markus Mitterhauser; Siegfried Kasper; Rupert Lanzenberger

Publication:     Brain Structure & Function, 2012

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Intrinsic cerebral connectivity analysis in an untreated female-to-male transsexual subject: a first attempt using resting-state fMRI

Background/aims: Transsexualism is a gender identity disorder whose symptomatology could involve cognitive, neurobiological and psychological variance from biological sex standard. Several evidences support the hypothesis of a structural and functional brain reorganization in transgender subjects, with a different impact for male-to-female and female-to-male (FtM) subjects. Here we used resting-state fMRI to understand the similarities between the spontaneous brain connectivity of an untreated FtM subject and two male and female control groups.

Methods: Both seed-voxel and atlas-based region-of-interest (ROI) approaches were used.

Results: Brain areas sensitive to gender dimorphism like left lingual gyrus and precuneus showed strong similarities between the FtM subject and female control group with respect to control males, with comparable extension and location of functional connectivity maps. ROI analysis confirmed this evidence, highlighting a greater pattern of differences between the FtM subject and males and the FtM subject and females. No difference between seed-voxel results in the FtM subject and females was found.

Conclusion: These data partially support the idea that untreated FtM transgender shows a functional connectivity profile comparable to female control subjects.

Author/-s:       E. Santarnecchi; G. Vatti; D. Déttore; A. Rossi

Publication:     Neuroendocrinology, 2012

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Increased Cortical Thickness in Male-to-Female Transsexualism

Background: The degree to which one identifies as male or female has a profound impact on one’s life. Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity. In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals.

Method: To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males.

Results: Results revealed thicker cortices in MTF transsexuals, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus).

Conclusion: These findings provide further evidence that brain anatomy is associated with gender identity, where measures in MTF transsexuals appear to be shifted away from gender-congruent men.

Author/-s:       Eileen Luders; Francisco J. Sánchez; Duygu Tosun; David W. Shattuck; Christian Gaser; Eric Vilain; Arthur W. Toga

Publication:     Journal of Behavioral and Brain Science, 2011

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White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study.

Background: Some gray and white matter regions of the brain are sexually dimorphic. The best MRI technique for identifying subtle differences in white matter is diffusion tensor imaging (DTI). The purpose of this paper is to investigate whether white matter patterns in female to male (FtM) transsexuals before commencing cross-sex hormone treatment are more similar to that of their biological sex or to that of their gender identity.

Method: DTI was performed in 18 FtM transsexuals and 24 male and 19 female heterosexual controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter fibers of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics.

Results: In controls, males have significantly higher FA values than females in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract.

Conclusions: Our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females). Our results provide evidence for an inherent difference in the brain structure of FtM transsexuals.

Author/-s:       Giuseppina Rametti; Beatriz Carrillo; Esther Gómez-Gil; Carme Junque; Santiago Segovia; Ángel Gomez; Antonio Guillamon

Publication:     Journal of Psychiatric Research, 2011

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Biological and psychosocial correlates of adult gender-variant identities: A review

This article reviews research on biological and psychosocial factors relevant to the etiology of gender-variant identities. There is evidence for a genetic component of gender-variant identities through studies of twins and other within-family concordance and through studies of specific genes. Evidence that prenatal androgens play a role comes from studies that have examined finger length ratios (2D:4D), prevalence of polycystic ovary syndrome among female-to-male transsexuals, and individuals with intersex and related conditions who are more likely to have reassigned genders. There is also evidence that transsexuals have parts of their brain structure that is typical of the opposite birth-assigned gender. A greater likelihood of non-right-handedness suggests developmental instability may also contribute as a biological factor. There is a greater tendency for persons with gender-variant identities to report childhood abuse and a poor or absent relationship with parents. It is unclear if this is a cause or effect of a gender-variant identity. Parental encouragement of gender-variance is more common among individuals who later develop a gender-variant identity. We conclude that biological factors, especially prenatal androgen levels, play a role in the development of a gender-variant identity and it is likely that psychosocial variables play a role in interaction with these factors.

Author/-s:       Jaimie F. Veale; David E. Clarke; Terri C. Lomax

Publication:     Personality and Individual Differences, 2010

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Dichotic Listening, Handedness, Brain Organization, and Transsexuality

This study investigated the functional brain organization of 68 male-to-female (MtF) transwomen and 26 female-to-male (FtM) transmen by comparing their performance with 36 typical male and 28 typical female controls on two indicators of cerebral lateralization: dichotic listening and handedness. A sex-differentiating dichotic test and a handedness questionnaire were administered. It was hypothesized that the MtF participants’ dichotic performance would be significantly different from the control males and resemble the control female pattern. This hypothesis was supported. It was also hypothesized that the FtM dichotic pattern would be significantly different from the control females and would resemble the control male pattern. This hypothesis was not supported. Finally, it was hypothesized that there would be significantly more nonexclusive right-handers in both trans-groups. This hypothesis was supported. Taken together, the dichotic and handedness data reported here indicate that the MtF and FtM conditions are not mirror images in terms of the verbal-auditory aspects of their brain organization and neurobiology plays an important role, particularly in the development of the male-to-female trans-condition.

Author/-s:       Ernest Govier; Milton Diamond; Teresa Wolowiec; Catherine Slade

Publication:     International Journal of Transgenderism, 2010

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EEG Analysis of Male to Female Transsexuals: Discriminant Function and Source Analysis

A small series of consecutive, unmedicated male to female transsexuals were studied before hormonal treatment and prior to reassignment surgery. Quantitative EEG and LORETA source localization in the Eyes Open and Eyes Closed conditions were carried out, and they were compared to sinistral/ambilateral male and female controls, as the transsexual group was overwhelmingly sinistral. Discriminant function analysis and source localization showed that the transsexual group was similar to female heterosexual controls, with increased sources in the right hemisphere in the fast frequencies.

Author/-s:       Pierre Flor-Henry

Publication:     Clinical EEG and Neuroscience, 2010

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Mentale Rotation bei Mann-zu-Frau-Transsexuellen und Männern ohne Geschlechtsidentitätsstörung – eine fMRT-Studie

Excerpt: This study shows that untreated MtF-TS show differences to the male control group in cortical activation. MtF-TS activated frontal and occipitotemporal areas more than male controls; male controls activated the lobus parietalis inferior of the left brain hemisphere more. The differences in activation are similar to the known differences between males and females. This could point to prenatal hormone fluctuations being one of many factors imprinting sexually dimorphic cortical functions and causing transsexualism.

Original: Es ist bekannt, dass Männer Frauen in räumlich-visuellen Fähigkeiten, vor allem in der mentalen Rotation dreidimensionaler Objekte, überlegen sind (Voyer et al., 1995). Diese Arbeit untersuchte elf Mann-zu-Frau-Transsexuelle (M-F-Transsexuelle) vor einer gegengeschlechtlichen Hormontherapie (HRT), elf M-F-Transsexuelle nach einer HRT und elf Männer ohne Geschlechtsidentitätsstörung (GIS). Mit den von Shepard und Metzler entworfenen dreidimensionalen Figuren wurden die kortikalen Aktivierungen mittels fMRT und die Leistungen in dem mentalen Rotationstest (Vandenberg und Kuse, 1978) erforscht.

Diese Arbeit konnte zeigen, dass schon im Vergleich von transsexuellen Männern vor HRT und Männern ohne GIS Unterschiede in der kortikalen Aktivierung bestehen. M-F-Transsexuelle vor HRT aktivierten vor allem frontale und occipitotemporale Areale stärker als Männer ohne GIS, während sich bei Männern ohne GIS im Vergleich zu M-F-Transsexuellen vor HRT Mehraktivierungen im Lobus parietalis inferior der linken Hemisphäre fanden. Es fielen bei den Aktivierungsunterschieden deutliche Parallelen zu den bekannten Aktivierungsunterschieden zwischen Männern und Frauen ohne GIS auf (Butler et al., 2006; Gizewski et al., 2006). Diese Beobachtungen liefern Indizien dafür, dass pränatale Hormonschwankungen möglicherweise ein Bestandteil der multifaktoriell bedingten Prägung sexuell dimorpher kortikaler Funktionen und der Entstehung der Transsexualität sein könnten.

Eine HRT bei M-F-Transsexuellen beeinflusste die kortikalen Aktivierungen in occipitotemporalen Arealen. Dennoch blieben die Aktivierungsunterschiede, die schon vor einer HRT zwischen M-F-Transsexuellen und Männern ohne GIS bestanden, vor allem in frontalen Arealen unverändert. Es wurden jedoch signifikante Leistungsunterschiede in der mentalen Rotation zwischen M-F-Transsexuellen nach HRT und Männern ohne GIS gefunden. Das repräsentiert einen aktivierenden Einfluss zirkulierender Geschlechtshormone auf kognitive Leistungen, der auch schon im Rahmen des Menstruationszykluses bei Frauen gesehen wurde (Hausmann et al., 2001).

Des Weiteren wurde in beiden transsexuellen Gruppen eine positive Korrelation zwischen der Höhe des Testosterons und der mentalen Rotationsleistung nachgewiesen. Dabei scheint das Testosteron vor allem parietale Areale zu beeinflussen.

Author/-s:       Christine Bauer

Publication:     Dissertation, Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, 2010

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Kognition bei Transsexualismus: Eine Studie mit Geschlechtsvergleich

Translation: Brain activation in during mental rotation and synonym formation was examined using fMRI.

Mental rotation (8 men, 7 women, 8 male-to-female transsexuals): Men activated parietally and frontally more than women. Further superior frontally, women activated more than men. Men also activated frontally and parietally more strongly than MF-TS. Women and MF-TS activated in the precuneus and right frontal gyrus medius more than men.

Synonym formation (each 6 men, women, MF-TS): Men activated frontally left and pre-centrally stronger than the women. The MF-TS activated, like the women, frontally left less than men. Temporally left both women and MF-TS activated less than men. Men and MF TS activated parietooccipital stronger than the women.

In summary, the MF-TS showed in many areas deviations compared to the men and similarities with the women. MF-TS probably have a different brain organization than men.

Original: Die Aktivierung im fMRT bei mentaler Rotation und Synonymbildung wurde untersucht.

Mentale Rotation (8 Männer, 7 Frauen, 8 Mann-zu-Frau-Transsexuelle): Die Männer aktivierten parietal und frontal stärker als die Frauen. Weiter superior frontal aktivierten die Frauen stärker als die Männer. Frontal und parietal aktivierten die Männer auch stärker als die MF-TS. Frauen und MF-TS aktivierten im Precuneus und Gyrus frontalis medius rechts stärker als die Männer.

Synonymbildung (je 6 Männer, Frauen, MF-TS): Die Männer aktivierten links frontal und präzentral stärker als die Frauen. Die MF-TS aktivierten wie die Frauen links frontal schwächer als die Männer. Temporal links aktivierten Frauen und MF-TS schwächer als die Männer. Männer und MF-TS aktivierten parietookzipital stärker als die Frauen.

Zusammenfassend zeigten die MF-TS in vielen Arealen Abweichungen zu den Männern und Gemeinsamkeiten mit den Frauen. Wahrscheinlich haben MF-TS eine von Männern abweichende Hirnorganisation.

Author/-s:       Eva Pletziger

Publication:     Dissertation, Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, 2009

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Specific Cerebral Activation due to Visual Erotic Stimuli in Male-to-Female Transsexuals Compared with Male and Female Controls: An fMRI Study

Introduction: Transsexuals harbor the strong feeling of having been born to the wrong sex. There is a continuing controversial discussion of whether or not transsexualism has a biological representation. Differences between males and females in terms of functional imaging during erotic stimuli have been previously described, revealing gender-specific results.

Aim: Therefore, we postulated that male-to-female (MTF) transsexuals may show specific cerebral activation differing from their biological gender.

Main Outcome Measure: Cerebral activation patterns during viewing of erotic film excerpts in functional magnetic resonance imaging (fMRI).

Methods: Twelve male and 12 female heterosexual volunteers and 12 MTF transsexuals before any treatment viewed erotic film excerpts during fMRI. Additionally, subjective rating of sexual arousal was assessed. Statistics were performed using the Statistical Parametric Mapping software.

Results: Significantly enhanced activation for men compared with women was revealed in brain areas involved in erotic processing, i.e., the thalamus, the amygdala, and the orbitofrontal and insular cortex, whereas no specific activation for women was found. When comparing MTF transsexuals with male volunteers, activation patterns similar to female volunteers being compared with male volunteers were revealed. Sexual arousal was assessed using standard rating scales and did not differ significantly for the three groups.

Conclusions: We revealed a cerebral activation pattern in MTF transsexuals compared with male controls similar to female controls compared with male controls during viewing of erotic stimuli, indicating a tendency of female-like cerebral processing in transsexualism.

Author/-s:       Elke R. Gizewski; Eva Renate Krause; Marc Schlamann; Friederike Happich; Mark E. Ladd; Michael Forsting; Wolfgang Senf

Publication:     The Journal of Sexual Medicine, 2009

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A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity

Transsexuality is an individual's unshakable conviction of belonging to the opposite sex, resulting in a request for sex-reassignment surgery. We have shown previously that the bed nucleus of the stria terminalis (BSTc) is female in size and neuron number in male-to-female transsexual people. In the present study we investigated the hypothalamic uncinate nucleus, which is composed of two subnuclei, namely interstitial nucleus of the anterior hypothalamus (INAH) 3 and 4. Post-mortem brain material was used from 42 subjects: 14 control males, 11 control females, 11 male-to-female transsexual people, 1 female-to-male transsexual subject and 5 non-transsexual subjects who were castrated because of prostate cancer. To identify and delineate the nuclei and determine their volume and shape we used three different stainings throughout the nuclei in every 15th section, i.e. thionin, neuropeptide Y and synaptophysin, using an image analysis system. The most pronounced differences were found in the INAH3 subnucleus. Its volume in thionin sections was 1.9 times larger in control males than in females (P < 0.013) and contained 2.3 times as many cells (P < 0.002). We showed for the first time that INAH3 volume and number of neurons of male-to-female transsexual people is similar to that of control females. The female-to-male transsexual subject had an INAH3 volume and number of neurons within the male control range, even though the treatment with testosterone had been stopped three years before death. The castrated men had an INAH3 volume and neuron number that was intermediate between males (volume and number of neurons P > 0.117) and females (volume P > 0.245 and number of neurons P > 0.341). There was no difference in INAH3 between pre-and post-menopausal women, either in the volume (P > 0.84) or in the number of neurons (P < 0.439), indicating that the feminization of the INAH3 of male-to-female transsexuals was not due to estrogen treatment. We propose that the sex reversal of the INAH3 in transsexual people is at least partly a marker of an early atypical sexual differentiation of the brain and that the changes in INAH3 and the BSTc may belong to a complex network that may structurally and functionally be related to gender identity.

Author/-s:       Alicia Garcia-Falgueras; Dick F. Swaab

Publication:     Brain – A journal of neurology, 2008

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See also a discussion of this study by Joe Herbert (Brain – A journal of neurology, 2008): “Who do we think we are? The brain and gender identity” (

Male-to-Female Transsexuals Show Sex-Atypical Hypothalamus Activation When Smelling Odorous Steroids

One working hypothesis behind transsexuality is that the normal sex differentiation of certain hypothalamic networks is altered. We tested this hypothesis by investigating the pattern of cerebral activation in 12 nonhomosexual male-to-female transsexuals (MFTRs) when smelling 4,16-androstadien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST). These steroids are reported to activate the hypothalamic networks in a sex-differentiated way. Like in female controls the hypothalamus in MFTRs activated with AND, whereas smelling of EST engaged the amygdala and piriform cortex. Male controls, on the other hand, activated the hypothalamus with EST. However, when restricting the volume of interest to the hypothalamus activation was detected in MFTR also with EST, and explorative conjunctional analysis revealed that MFTR shared a hypothalamic cluster with women when smelling AND, and with men when smelling EST. Because the EST effect was limited, MFTR differed significantly only from male controls, and only for EST-AIR and EST-AND. These data suggest a pattern of activation away from the biological sex, occupying an intermediate position with predominantly female-like features. Because our MFTRs were nonhomosexual, the results are unlikely to be an effect of sexual practice. Instead, the data implicate that transsexuality may be associated with sex-atypical physiological responses in specific hypothalamic circuits, possibly as a consequence of a variant neuronal differentiation.

Author/-s:       H. Berglund; P. Lindström; Cecilia Dhejne-Helmy; Ivanka Savic

Publication:     Cerebral Cortex, 2008

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Phantom penises in transsexuals

How the brain constructs one’s inner sense of gender identity is poorly understood. On the other hand, the phenomenon of phantom sensations – the feeling of still having a body-part after amputation – has been much studied. Around 60 % of men experience a phantom penis post-penectomy. As transsexuals report a mismatch between their inner gender identity and that of their body, we won-dered what could be learnt from this regarding innate gender-specific body image. We surveyed male-to-female transsexuals regarding the incidence of phantoms post-gender reassignment surgery. Addition-ally, we asked female-to-male transsexuals if they had ever had the sensation of having a penis when there was not one physically there. In post-operative male-to-female transsexuals the incidence of phan-tom penises was significantly reduced at 30 %. Remarkably, over 60 % of female-to-male transsexuals also reported phantom penises. We explain the absence/presence of phantoms here by postulating a mis-match between the brain's hardwired gender-specific body image and the external somatic gender. Further studies along these lines may provide penetrating insights into the question of how nature and nurture interact to produce our brain-based body image.

Author/-s:       V. S. Ramachandran

Publication:     Journal of Consciousness Studies, 2008

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Geschlechtsspezifische Differenzen der Hirnaktivität in der fMRT bei Normalprobanden im Vergleich mit transsexuellen Probanden

Excerpt: Regions of interest in the brain defined prior to this study showed clear differences between the genders. Differences between MtF transsexuals and male controls in the activation pattern of the erotic paradigm were similar to differences between male controls and female controls. No significant differences were found between MtF transsexuals and female controls when erotically stimulated. Furthermore, statistical comparisons of the results of the mental rotation task showed marked gender differences. FMRI with the paradigms used proved to be a useful tool for analysing gender differences. For the first time, this study showed that MtF transsexuals have a female cortical activation pattern when watching erotic movies; even before hormonal treatment.

Original: Männer und Frauen unterscheiden sich in ihren Verhaltens- und Reaktionsweisen. Zahlreiche psychologische Studien bestätigen Geschlechtsunterschieden auf verschiedenen Ebenen. Neuroradiologische Untersuchungen zeigten auch in der kortikalen Aktivität Geschlechtsdifferenzen. Als geeignete Stimuli, derartige geschlechtsabhängige Aktivierungen zu reproduzieren, erwiesen sich erotische Reize und Aufgaben zum räumlichen Denken. In der vorliegenden Studie wurden 12 Männer, 12 Frauen und 12 Mann-zu-Frau-Transsexuelle mit Funktioneller Magnetresonanztomographie (fMRT) untersucht. Den Probanden wurden als Stimuli Ausschnitte aus erotischen Filmen und ein zweidimensionaler Mental Rotation Task präsentiert. Per Fragebögen wurden die Eignung der Probanden für die Untersuchung und Eckdaten zum Körperbild erhoben, auf einer visuellen Analogskala gaben die Probanden das Maß der sexuellen Erregung sowie der Aufmerksamkeit an. Die statistische Nachbearbeitung und Auswertung der Daten erfolgte mit SPM (Statistical Parametric Mapping) 99 Software. Für das erotische Paradigma wurde eine einfache vergleichende Statistik (two-sample-t-test) durchgeführt sowie eine Multiple Regression berechnet. Das angegebene Maß der sexuellen Erregung floss als Kovariate in die Berechnungen ein. Für beide Paradigmen bestätigten sich die aus vorherigen Studien bekannten, zu den jeweiligen Stimuli gehörenden Areale. In den a priori definierten ROI (Regions of Interest) zeigten sich deutliche Geschlechtsunterschiede. Die Gruppe der männlichen Probanden wies in dem erotischen Paradigma signifikant höhere Aktivierungen im linken Thalamus, in der Amygdala beidseits, im orbitofrontalen Kortex beidseits, im anterioren Cingulum, in der Insula beidseits und parahippocampal auf. Frauen, die in der Mitte ihres Menstruationszyklus die Untersuchung durchliefen, zeigten auf gleichem Signifikanzniveau (p = 0,001 unkorrigiert) keine stärkeren Aktivierungen im Vergleich zu den Männern. Im Vergleich zu den Transsexuellen wiesen die männlichen Probanden im erotischen Paradigma ein ähnliches Aktivierungsmuster auf wie im Vergleich zu den Frauen. Zwischen Transsexuellen und weiblichen Probanden zeigten sich bei erotischem Stimulus keine signifikanten Unterschiede. Auch die vergleichende Statistik der Ergebnisse des Mental Rotation Task enthüllte deutliche Geschlechtsdifferenzen. Männer zeigten signifikant stärkere Aktivierungen im medialen temporalen, mittleren frontalen, linken inferioren parietalen sowie präzentralen Kortex. Frauen wiesen in diesem Paradigma stärkere Aktivierungen bilateral im superioren frontalen Kortex, im rechten inferioren Parietallappen sowie links im postzentralen Kortex auf. Die fMRT mit den benutzten Paradigmen erwies sich als geeignetes Instrument zur Erfassung von Geschlechtsdifferenzen. Zum ersten Mal konnte in dieser Studie gezeigt werden, dass Mann-zu-Frau-Transsexuelle bereits vor Behandlung ein weibliches kortikales Aktivierungsmuster beim Betrachten erotischer Filme aufweisen. Die fMRT könnte aufgrund der vorliegenden Ergebnisse in Zukunft Bedeutung erlangen für Diagnostik und Therapie der Transsexualität.

Author/-s:       Eva Renate Krause

Publication:     Dissertation, Medizinische Fakultät, Universität Duisburg-Essen, 2007

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Callosal Shapes at the Midsagittal Plane: MRI Differences of Normal Males, Normal Females, and GID

We investigated differences in corpus callosum shape at the midsagittal plane using MRI for different subjects: normal males, normal females, and subjects with gender identity disorder (GID). We first represented callosal shapes with Fourier descriptors of callosal contours. Using linear support vector machines with soft-margin, we next determined a hyperplane that separates normal males and females most optimally in the vector space spanned by Fourier descriptors. We then proposed a measure that has prominent sex difference: it is defined as the coordinate of a given callosal shape on the subspace orthogonal to the obtained hyperplane. Use of the measure provides discrimination of someone's sex with 74.17 % accuracy. We further showed that the value of the measure for GID more strongly reflects their mental sex, i.e. gender, than their physical sex.

Author/-s:       Y. Yokota; Y. Kawamura; Y. Kameya

Publication:     Conference Proceedings, IEEE Engineering in Medicine and Biology Society, 2005

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Sex in the brain. Gender differences in the human hypothalamus and adjacent areas. Relationship to transsexualism, sexual orientation, sex hormone receptors and endocrine status.

Summary of Chapter 1: From the moment of conception until the moment we die we are living in a sex-differentiated world. Not only do men and women have different physiques, they also have sex differences in seeing, smelling, thinking, feeling, behaving, socializing and making love. Thee brain orchestrates these sex differences by irreversible structural ("organizational") and reversible ("activational") sex differences. Examples of such differences are macroscopically sex differences in brain volume, weight and regional differences in size, shape or fiber connections. Microscopically sex differences may exist e.g. in neuronal cell numbers, perikaryal size, dendritic branching and synaptogenesis, while at the molecular level sex differences can exist e.g. at the level of neuropeptides, neurotransmitters, enzymes, proteins and mRNA.. Functional sex differences exist in various aspects of reproduction (e.g. in the presence of the menstrual cycle in the hypothalamo-pituitary-gonadal- [HPG]-- axis in women), gender identity (i.e. the feeling to be male or female), sexual orientation (i.e. hetero-, bi-, or homosexuality), autonomic functions (differences in e.g. biological rhythms in body temperature, stress hormones, bloodpressure and sleep) as well as in sex hormone dependent gender differences in the regulation of mood, cognition, behaviour and neuroprotection in health and disease. The present thesis was undertaken to investigate structural and functional differences in the human hypothalamus and adjacent areas in relation to sex, gender identity and sexual orientation by focussing on morphological sex differences, sex hormone receptors (i.e. estrogen receptor- alpha [ERa], beta [ER0], androgen receptors [ARs] and progesterone receptors [PRs]) and their relation to endocrine status. To this end potential structural sex differences were studied inn human post mortem brain material by volume measurements and neuron counts (Chapter 2), while, as a basis for the detection of their site of action and thee mechanisms involved in the functional sex differences, differences in the expression of gonadal hormone receptors were studied immunocytochemically (Chapters 3–8).

Summary of Chapter 2: First the central part of the human bed nucleus of the stria terminal is (BSTc) was studied in order to determine whether its previously reported sex difference in size and its striking sex reversed size in transsexual subjects were also reflected in neuronal numbers. Transsexuals experience themselves as being off the opposite sex, in spite of having all the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported, gender identity related, female size of the central part of the bed nucleus of the stria terminalis (BSTc) was based upon a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide (VIP) innervation from the amygdala and other areas, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin (SOM) expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity and hormonal status. Regardless of sexual orientation men had almost twice as many somatostatin neurons in the BSTcc as women (p<0.006). The number of neurons in the BSTc of male-to-female transsexual was similar to that of the females (p=0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.

Summary of Chapter 3: The next step was to find out whether the BSTc and other hypothalamic areas are sex hormone sensitive as judged by the presence of gonadal hormone receptors. For this purpose immunohistochemical protocols for paraffin embedded formalin fixed hypothalamic human brain material were developed. First androgen receptor (AR) distribution was described throughout the rostro-caudal hypothalamus and adjacent areas. In this chapter we report for the first time the distribution of androgen receptor immunoreactivity (AR-ir) in the human hypothalamus of 10 human subjects (5 men and 5 women) ranging between 20 and 399 years of age using the antibody PG21. Prolonged post mortem delay (72:00 hours)) or fixation time (100 days) did not influence the AR-ir. In men, intense nuclear AR-ir was found in neurons of the horizontal limb of the diagonal band off Broca, of the lateromamillary nucleus (LMN) and in the medial mammillary nucleus (MMN). An intermediate nuclear staining was found in the diagonal band of Broca, sexually dimorphic nucleus of the preoptic area, paraventricular nucleus, suprachiasmatic nucleus, ventromedial nucleus and infundibular nucleus, while weaker labelling was found in the bed nucleus of the stria terminalis, medial preoptic area, dorsal and ventral zone of the periventricular nucleus, supraoptic nucleus and nucleus basalis of Meynert. In most brain areas women revealed less staining than men. In the LMN and the MMN a strong sex difference was found. Cytoplasmic labelling was observed in neurons of both sexes, while women showed a higher variability in the intensity of such staining. No six differences in AR-ir were, however, observed in the bed nucleus of the stria terminalis, the nucleus basalis of Meynert (NBM) and islands of Calleja. Species differences and similarities of the AR-ir distribution were discussed. The present results suggest the participation of androgens in the regulation of various hypothalamic processes that are sexually dimorphic.

Summary of Chapter 4: In the previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally men had a stronger nuclear androgen receptor immunoreactivity (AR-ir) than women. The strongest nuclear labelling was found in the caudal hypothalamus in the mamillary body complex (MBC), which is known to be involved in aspects of sexual behaviour. The study in this chapter was carried out to investigate whether the sex difference in AR-ir of the MBC is related to sexual orientation or gender identity (i.e. the feeling to be male or female) or rather to circulating levels of androgens, since nuclear AR-ir is known to be upregulated by androgens from animal experiments. Therefore, we studied the MBC in the following groups: young-heterosexual men, young-homosexual men, aged-heterosexual castrated and non-castrated men, castrated and non-castrated transsexuals, young-heterosexual women and a young virilized woman. Nuclear AR-ir did not differ significantly between heterosexual and homosexual men but was significantly stronger in men than in women. A female-like pattern of AR-ir (i.e. no to weak nuclear staining) was observed in 26 to 53 year old castrated male-to-female transsexuals and in old castrated and non-castrated males of 67 to 87 years of age. In analogy with animal studies showing strong activational effects of androgens on nuclear AR-ir, the present data suggest that nuclear AR-ir in the human MBC is dependent on the presence or absence of circulating levels of androgens. The group data were, moreover, supported by the fact that a male-like AR-ir (i.e. intense nuclear AR-ir), was found in a 36 year old bisexual non-castrated male-to-female transsexual and in a heterosexual virilized woman off 46 years of age with high levels of circulating testosterone. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these alterations are discussed in relation to reproduction, cognition and neuroprotection.

Summary of Chapter 5: In 1996 a novel second genomic ER subtype of ERs was cloned in rodents and humans and designed ERp. Subsequently it has been demonstrated that the original 'classical' ERa and the second ERp subtype may play different often opposite (e.g. activating [ERa] versus inhibiting [ERp]) roles in gene regulation. In order to determine the putative sites of action of estrogens, mediated by Era and ERp in the human hypothalamus and adjacent areas immunocytochemical protocols were developed for systematic rostro-caudal mapping studies in relation to sex and endocrine status in the same young adults studied for AR-ir in chapter 3. Hypothalamic material taken from 10 subjects (5 men and 5 women), ranging between 20 and 39 years of age, was investigated. Since it is known from various animal and human studies that ERs can be down- or upregulated by circulating levels of estrogens in a region dependent way, hypothalami of a few rare cases with well documented abnormal estrogen levels were also studied: a castrated, estrogen treated 50 year old male-to-female transsexual (Tl), a 31 year old man with an estrogen producing tumor (S2) and an ovariectomized 46 year old woman (S8). A strong sex difference with more nuclear ERa-ir in women was observed rostrally in the diagonal band of Broca (DBB) and caudally in the medial mamillary nucleus (MMN). Less robust sex differences were observed in other brain areas with more intense nuclear ERa-ir in men, e.g., in the sexually dimorphic nucleus of the medial preoptic area (SDN-POA), paraventricular nucleus (P VN) and lateral hypothalamic area (LHA), while women had more nuclear ERa-ir inn the suprachiasmatic nucleus (SCN) and ventromedial nucleus (VMN). No nuclear sex differences in ERa were found e.g. in the central part of the BST (BSTc). In addition to nuclear staining, ERa-ir appeared to also be sex-dependently present in the cytoplasm of neurons and was observed in astrocytes, plexus choroideus and vascular cells. The differences in ERa-ir in subjects T1, S2 and S8 indicated the presence off some activating effects of estrogens on hypothalamic ERa-ir. The female expression pattern of ERa-ir in the VMN and MMN of the genetic male subjects (Tl) and (S2) (see e.g. Fig. 14C) were related to higher circulating estrogen levels. On the other hand, no clear changes occurred in the BSTc, SDNN or DBB, and a strikingly low ERa-ir was found in the NBM (cf Fig. 7E; Fig.. 8A; Fig. 11 A). These data seem to suggest that in addition to differential activational effects of estrogen on ERa-ir, also other regulatory mechanisms (that are independent on circulating estrogen levels occur, such as effects on an organizational level) might be involved in the regional control of some ERa-ir sexx differences. However, ERa-ir in T1, S2 and S8 suggested that the majority off the observed sex differences in ERa-ir are "activational" (e.g., VMN/MMN) rather than "organizational" in nature. Species similarities and differences in ERa-ir distribution and possible functional implications for the human brain are discussed.

Summary of Chapter 6: Subsequently a systematic rostro-caudal distribution of ERp-ir was studied in the human hypothalamus and adjacent areas in 5 males and 5 females between 20–39 years of age and compared to the ERa distribution (Chapter 5)) in the same patients. ER0-ir was generally observed more frequently in the cytoplasm than in the nucleus and appeared to be stronger in women. In addition, basket-like fiber stainings, suggestive for ERp-ir in synaptic-terminals, were observed in various areas. Men showed more robust nuclear ERp-ir than women in the medial part of the bed nucleus of the stria terminalis (BSTm), paraventricular and paratenial nucleus of the thalamus (PV and PT), while less intense, but more nuclear, ERp-ir appeared to be present in e.g. the BSTc, SDN-POA, DBB and VMN. Women revealed more nuclear ERp-ir than men of a low to intermediate level e.g. in the SCN, supraoptic (SON), PVN, infundibular (INF) and MMN. ERp-irr expression patterns in subjects with abnormal hormone levels, i.e., a 50 year old castrated estrogen treated male-to-female transsexual, a 31 year old man with an estrogen producing tumor and a 46 year old ovariectomized woman, suggest that the majority of the observed sex differences in ERp-ir are "activational" rather than "organizational" in nature. Similarities, differences, potential functional and clinical implications of the observed sex and hormone dependent ERa and ERp distributions are discussed in relation to reproduction, autonomic-function, mood, cognition and neuroprotection in health and disease.

General discussion – Transsexuality: Transsexual individuals have the strong feeling, often from their earliest childhood memories onwards, of having been born the wrong sex. Gender identity disorder (GID) as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) consists of two components: (1) a strong and persistent cross-gender identification and (2) persistent discomfort with one’s biological sex or gender role behavior associated with one’s sex. The most extreme form, in which individuals need to adapt their phenotype with hormones and surgery to make it congruent with their gender identity, is called transsexualism (cf. 'Definition and Synopsis of the Etiology of Gender Identity Disorder and Transsexualism': Transsexualism is thus the condition in which the transsexual person is convinced that he or she is actually a member of the opposite sex (reviewed by Gooren and Kruijver, 2002). Transsexuality is a rare condition. The annual incidence of transsexuality has been estimated in Sweden to be about 1/500 0000 inhabitants. The sex ratio (genetic male:female) has been shown to vary from country to country between 1.4:1 and 3:1 (Landen et al., 1996; Garrels et al., 2000). In the Netherlands the prevalence of MTFs was found to be 1: 111 900 and 1: 30 400 for FTMs (Bakker et al., 1993). The frequency of regret cases of sex re-assigned transsexual individuals varies from 3.8 % in Sweden (Landen, 1999) to 0.4 % in Germany and The Netherlands (Weitze and Osburg, 1996; van Kesteren et al., 1996). Transsexualism cannot be explained, in general, by variations in gonadal, genital or hormonal systems in adulthood (Gooren, 1990; Cohen-Kettenis and Gooren, 1999). In most cases, it cannot be clearly explained by variations in chromosomal patterns either (Gooren, 1990; Cohen-Kettenis and Gooren, 1999), although recent studies identified some sex chromosome anomalies. Six cases of male-to-female transsexuals with 47, XYY chromosome and one female-to-male transsexual with 47, XXX have been reported (Tayfun Turan et al., 2000). Also in men with Klinefelter syndrome (47, XXY) transsexualism has been reported (Wyler et al., 1979; Seifert and Windgassen, 1995). A recent study on gender identity disorder (GID) in a child and adolescent mono- (n=96) and di-zygotic (N=61) pooled twin sample supports moreover the hypothesis that there is a heritable component to GID (Coolidge et al., 2002). This study also fits with other recent studies pointing to pairs of monozygotic female twins requesting for sex reassignment therapy and with familial cases of gender identity problems (Green, 2000; Sadeghi and Fakhrai, 2000). Together, these data do suggest a genetic basis in at least a subpopulation of transsexual people (reviewed by Swaab, 2002).

General discussion – The paradigm of transsexuality as a neuro-developmental condition: “The brain is the sexiest hidden organ that we have” – Frank P.M. Kruijver, 2002.

As pointed out in the introduction, sexual differentiation is a sequential process. At conception the configuration of the sex chromosomes determines the genetic sex, the genetic sex determines the gonadal sex and the gonadal sex influences the brain sex by gender specific secretion patterns of sex hormones: male by the presence of testicular androgens, female by the absence of testis and the lack of peaks in testicular androgen exposure, i.e. prenatally around 12–24 weeks of gestational age and postnatally around 4–24 weeks of neonatal age (reviewed by Hrabovszky and Hutson, 2002). The present thesis shows that the human limbic brain expresses regional sex differences in gonadal hormone receptors (Chapter 3–8). Also during early development sex hormone receptors are present in the human brain in a stage-dependent sexually dimorphic way (cf. Chung, 2003). It thus appears conceivable that due to local hormone dependent changes during development at least some areas of the brain may follow a different course than the genitals during the process of sexual differentiation. A partial or even complete brain-body sex reversal may eventually be the result. This could lead to the development of female-like brain structures in a brain of a subject so far male differentiated or vice versa. If these brain areas are particularly involved in the establishment of e.g. an individual’s sexual orientation or gender identity a sex reversed partner preference or gender identity may be the result. The present thesis has provided new neurobiological evidence to support the view that transsexualism can be explained by a sex reversed brain status.

Author/-s:       Frank P. M. Kruijver

Publication:     Dissertation, Faculty of Medicine, University of Amsterdam, 2004

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Organizing and activating effects of sex hormones in homosexual transsexuals

The cause of transsexualism remains unclear. The hypothesis that atypical prenatal hormone exposure could be a factor in the development of transsexualism was examined by establishing whether an atypical pattern of cognitive functioning was present in homosexual transsexuals. Possible activating effects of sex hormones as a result of cross-sex hormone treatment were also studied. Female-to-male and male-to-female transsexuals were compared with female and male controls with respect to spatial ability before and after treatment. The data were consistent with an organizing effect, but there was no evidence of an activating effect. Homosexual transsexuals, who prior to hormone treatment scored in the direction of the opposite sex, may have reached a ceiling in performance and therefore do not benefit from activating hormonal effects.

Author/-s:       Stephanie H. M. van Goozen; Ditte Slabbekoorn; Louis J. G. Gooren; G. Sanders; Peggy T. Cohen-Kettenis

Publication:     Behavioral neuroscience, 2002

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Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic Nucleus

Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis (BSTc) was based on a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin-expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity, and past or present hormonal status. Regardless of sexual orientation, men had almost twice as many somatostatin neurons as women (P < 0.006). The number of neurons in the BSTc of male-to-female transsexuals was similar to that of the females (P = 0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.

Author/-s:       Frank P. M. Kruijver; Jiang-Ning Zhou; Chris W. Pool; Michel A. Hofman; Louis J. G. Gooren; Dick F. Swaab

Publication:     The Journal of Clinical Endocrinology & Metabolism, 2000

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A sex difference in the human brain and its relation to transsexuality

Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psycho-genie or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.

Author/-s:       Jiang-Ning Zhou; Michel A. Hofman; Louis J. G. Gooren; Dick F. Swaab

Publication:     Nature, 1995

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