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ArticleAuthorYearJournal & Impact FactorCitations & AltmetricAbstractNotesOpen accessLink
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Alterations in the inferior fronto-occipital fasciculus – a specific neural correlate of gender incongruence?van Heesewijk, Steenwijk, Kreukels, Veltman, Bakker, Burke2022Psychological Medicine7.72302Background
Increasing numbers of adolescents seek help for gender-identity questions. Consequently, requests for medical treatments, such as puberty suppression, are growing. However, studies investigating the neurobiological substrate of gender incongruence (when birth-assigned sex and gender identity do not align) are scarce, and knowledge about the effects of puberty suppression on the developing brain of transgender youth is limited.

Methods
Here we cross-sectionally investigated sex and gender differences in regional fractional anisotropy (FA) as measured by diffusion MR imaging, and the impact of puberty on alterations in the white-matter organization of 35 treatment-naive prepubertal children and 41 adolescents with gender incongruence, receiving puberty suppression. The transgender groups were compared with 79 age-matched, treatment-naive cisgender (when sex and gender align) peers.

Results
We found that transgender adolescents had lower FA in the bilateral inferior fronto-occipital fasciculus (IFOF), forceps major and corpus callosum than cisgender peers. In addition, average FA values of the right IFOF correlated negatively with adolescents' cumulative dosage of puberty suppressants received. Of note, prepubertal children also showed significant FA group differences in, again, the right IFOF and left cortico-spinal tract, but with the reverse pattern (transgender > cisgender) than was seen in adolescents.

Conclusions
Importantly, our results of lower FA (indexing less longitudinal organization, fiber coherence, and myelination) in the IFOF of gender-incongruent adolescents replicate prior findings in transgender adults, suggesting a salient neural correlate of gender incongruence. Findings highlight the complexity with which (pubertal) sex hormones impact white-matter development and add important insight into the neurobiological substrate associated with gender incongruence.		Yesfull text
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The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working GroupMueller, Guillamon, Zubiaurre-Elorza, Junque, Gomez-Gil, Uribe, Khorashad, Khazai, Talaei, Habel, Votinov, Derntl, Lanzenberger, Seiger, Kranz, Kreukels, Cohen Kettenis, Burke, Lambalk, Veltman, Kennis, Sánchez, Vilain, Fisher, Mascalchi, Gavazzi, Orsolini, Ristori, Dannlowski, Grotegerd, Konrad, Schneider, T'Sjoen, Luders2021The Journal of Sexual Medicine3.8021243Background
In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings.

Aim
To examine the neurobiology of transgender persons in a large sample.

Methods
Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed.

Outcomes
Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness.

Results
Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined.

Clinical Translation
The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies.

Strengths and Limitations
While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites.

Conclusion
Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype.		Nofull text (via sci-hub)
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Neurobiology of Pediatric Gender IdentityKreukels, Burke2021Pediatric Gender IdentityN/A41Our understanding of the neurobiological basis of gender diversity is limited. Even though more and more neuroimaging studies in adults hint towards sex-atypical and less pronounced sexual differentiation, the picture is far from clear and relatively little is known about the neurobiological correlates of gender incongruence in childhood and youth. In addition, recent studies in adults challenge atypical sexual differentiation of the brain as a sole neurobiological explanation of the condition, also suggesting alterations in brain regions processing self- and body-awareness. Furthermore, the interplay between neurobiological and psychosocial factors in the development of diverse gender identities is poorly understood. In this chapter, we review the literature investigating mechanisms that may underlie gender diversity from a neurobiological perspective. In the first section, we focus on genetic factors that may contribute to gender diverse behaviour and gender identity development. Based on heritability studies, a hypothesis is formulated that there is not one single gene that accounts for the development of gender identity, but many genes are asserted to contribute in addition to other factors that are non-genetic. Next, principles of the prominent sexual differentiation hypothesis of gender incongruence will be discussed. We will summarize the evidence for sex-atypical differentiation of brain function and structure among transgender and gender diverse youth. Moreover, findings with regard to the effects of gender-affirming hormonal treatment on the brain will be presented. We will close the chapter with future directions for research into the neurobiology of gender diversity.Review (book chapter)Nofull text (via sci-hub)
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Postnatal Effects of Sex Hormones on Click-Evoked Otoacoustic Emissions: A Study of Adolescents with Gender DysphoriaBurke, van Heesewijk, Menks, Klink, Kreukels, Cohen-Kettenis, Bakker2020Archives of Sexual Behavior4.50732Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to originate from testosterone influences during prenatal male sexual differentiation and to remain stable throughout life. However, recent studies suggested activational, postnatal effects of sex hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment. Using a cross-sectional design, we examined whether hormonal interventions in adolescents diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age- and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were observed among cisgender controls and treatment-naïve trans boys but not in other groups with GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs compared with control girls. A similar trend was seen in trans boys treated with GnRHa only. Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure as they can be modulated postnatally by sex hormones, in the form of hormonal treatment.Follow-up to Burke, et al. 2014, "Click-Evoked Otoacoustic Emissions in Children and Adolescents with Gender Identity Disorder", suggesting that CEOAEs are affected post-natally by HRT and may not be a reliable marker for innate GD as previously suggested.Yesfull text
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Neural Systems for Own-body Processing Align with Gender Identity Rather Than Birth-assigned SexMajid, Burke, Manzouri, Moody, Dhejne, Feusner, Savic2020Cerebral Cortex5.0431330Gender identity is a core aspect of self-identity and is usually congruent with birth-assigned sex and own body sex-perception. The neuronal circuits underlying gender identity are unknown, but greater awareness of transgenderism has sparked interest in studying these circuits. We did this by comparing brain activation and connectivity in transgender individuals (for whom gender identity and birth-assigned sex are incongruent) with that in cisgender controls (for whom they are congruent) when performing a body self-identification task during functional magnetic resonance imaging. Thirty transgender and 30 cisgender participants viewed images of their own bodies and bodies morphed in sex toward or opposite to birth-assigned sex, rating each image to the degree they identified with it. While controls identified with images of themselves, transgender individuals identified with images morphed “opposite” to their birth-assigned sex. After covarying out the effect of self-similarity ratings, both groups activated similar self- and body-processing systems when viewing bodies that aligned with their gender identity rather than birth-assigned sex. Additionally, transgender participants had greater limbic involvement when viewing ambiguous, androgynous images of themselves morphed toward their gender identity. These results shed light on underlying self-processing networks specific to gender identity and uncover additional involvement of emotional processing in transgender individuals.Yesfull text
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Neuroimaging gender dysphoria: a novel psychobiological modelAltinay, Anand2019Brain Imaging And Behavior3.978732Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology of GD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis of GD; which leads to the concept of brain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals’ interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development of GD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.ReviewNofull text (via sci-hub)
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Genetic Link Between Gender Dysphoria and Sex Hormone SignalingForeman, Hare, York, Balakrishnan, Sánchez, Harte, Erasmus, Vilain, Harley2019The Journal of Clinical Endocrinology & Metabolism5.95834368Context
There is a likely genetic component to gender dysphoria, but association study data have been equivocal.

Objective
We explored the specific hypothesis that gender dysphoria in transgender women is associated with variants in sex hormone–signaling genes responsible for undermasculinization and/or feminization.

Design
Subject-control analysis included 380 transgender women and 344 control male subjects. Associations and interactions were investigated between functional variants in 12 sex hormone–signaling genes and gender dysphoria in transgender women.

Setting
Patients were recruited from the Monash Gender Clinic, Monash Health, Melbourne, Australia, and the University of California, Los Angeles.

Patients
Caucasian (non-Latino) transgender women were recruited who received a diagnosis of transsexualism [Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV) or gender dysphoria (DSM-V)] pre- or postoperatively. Most were receiving hormone treatment at the time of recruitment.

Main Outcome Measured
Genomic DNA was genotyped for repeat length polymorphisms or single nucleotide polymorphisms.

Results
A significant association was identified between gender dysphoria and ERα, SRD5A2, and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele combinations were also overrepresented in transgender women, most involving AR (namely, AR-ERβ, AR-PGR, AR-COMT, CYP17-SRD5A2). Overrepresented alleles and genotypes are proposed to undermasculinize/feminize on the basis of their reported effects in other disease contexts.

Conclusion
Gender dysphoria may have an oligogenic component, with several genes involved in sex hormone–signaling contributing.		Yesfull text
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Cross sex hormone treatment is linked with a reversal of cerebral patterns associated with gender dysphoria to the baseline of cisgender controlsKilpatrick, Holmberg, Manzouri, Savic2019European Journal of Neuroscience3.3861527Transgender persons experience incongruence between their gender identity and birth-assigned sex. The resulting gender dysphoria (GD), is frequently treated with cross-sex hormones. However, very little is known about how this treatment affects the brain of individuals with GD, nor do we know the neurobiology of GD. We recently suggested that disconnection of fronto-parietal networks involved in own-body self-referential processing could be a plausible mechanism, and that the anatomical correlate could be a thickening of the mesial prefrontal and precuneus cortex, which is unrelated to sex. Here, we investigate how cross-sex hormone treatment affects cerebral tissue in persons with GD, and how potential changes are related to self-body perception. Longitudinal MRI measurements of cortical thickness (Cth) were carried out in 40 transgender men (TrM), 24 transgender women (TrW) and 19 controls. Cth increased in the mesial temporal and insular cortices with testosterone treatment in TrM, whereas anti-androgen and oestrogen treatment in TrW caused widespread cortical thinning. However, after correction for treatment-related changes in total grey and white matter volumes (increase with testosterone; decrease with anti-androgen and oestrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs. controls) – regions showing greater pre-treatment Cth than in controls. The own body – self congruence ratings increased with treatment, and correlated with a left parietal cortical thinning. These data confirm our hypothesis that GD may be associated with specific anatomical features in own-body/self-processing circuits that reverse to the pattern of cisgender controls after cross-sex hormone treatment.Abnormalities in the "own-body/self-processing circuits" of the brain are implicated in gender dysphoria.Nofull text (via sci-hub)
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Brain structure and function in gender dysphoriaBakker2018Endocrine AbstractsN/A410The concept of gender identity is uniquely human. Hence we are left with the phenomenon of men and women suffering from Gender Dysphoria (GD) also known as transsexualism to study the origins of gender identity in humans. It has been hypothesized that atypical levels of sex steroids during a perinatal critical period of neuronal sexual differentiation may be involved in the development of GD. In order to test this hypothesis, we investigated brain structure and function in individuals diagnosed with GD using magnetic resonance imaging (MRI). Since GD is often diagnosed in childhood and puberty has been proposed to be an additional organizational period in brain differentiation, we included both prepubertal children and adolescents with GD in our studies. First, we measured brain activation upon exposure to androstadienone, a putative male chemo-signal which evokes sex differences in hypothalamic activation (women > men). We found that hypothalamic responses of both adolescent girls and boys diagnosed with GD were more similar to their experienced gender than their birth sex, which supports the hypothesis of a sex-atypical brain differentiation in these individuals. At the structural level, we analyzed both regional gray matter (GM) volumes and white matter (WM) microstructure using diffusion tensor imaging. In cis-gender girls, larger GM volumes were observed in the bilateral superior medial frontal and left pre/postcentral cortex, while cis-gender boys had more volume in the bilateral superior-posterior cerebellum and hypothalamus. Within these regions of interest representing sexually dimorphic brain structures, GM volumes of both GD groups deviated from the volumetric characteristics of their birth sex towards those of individuals sharing their gender identity. Furthermore, we found intermediate patterns in WM microstructure in adolescent boys with GD, but only sex-typical ones in adolescent girls with GD. These results on brain structure are thus partially in line with a sex-atypical differentiation of the brain during early development in individuals with GD, but might also suggest that other mechanisms are involved. Indeed, using resting state MRI, we observed GD-specific functional connectivity in the visual network in adolescent girls with GD. The latter is in support of a more recent hypothesis on alterations in brain networks important for own body perception and self-referential processing in individuals with GD.Preliminary findings presented at the European Congress of Endocrinology ECE 2018 conference and not published in a journal. Demonstrates atypical sex-differentiation of the brain in pre-puberty, pre-treatment children with Gender Dysphoria, strongly suggesting that there is an innate neurological correlate to GD without the influence of postnatal sex hormones. Also posits that it is hypothetically possible to diagnose GD based on MRI scans.Noabstract only
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Molecular basis of Gender Dysphoria: androgen and estrogen receptor interactionFernández, Guillamon, Cortés-Cortés, Gómez-Gil, Jácome, Esteva, Almaraz, Mora, Aranda, Pásaro2018Psychoneuroendocrinology4.9052695Background
Polymorphisms in sex steroid receptors have been associated with transsexualism. However, published replication studies have yielded inconsistent findings, possibly because of a limited sample size and/or the heterogeneity of the transsexual population with respect to the onset of dysphoria and sexual orientation. We assessed the role of androgen receptor (AR), estrogen receptors alpha (ERα) and beta (ERβ), and aromatase (CYP19A1) in two large and homogeneous transsexual male-to-female (MtF) and female-to-male (FtM) populations.

Methods
The association of each polymorphism with transsexualism was studied with a twofold subject-control analysis: in a homogeneous population of 549 early onset androphilic MtF transsexuals versus 728 male controls, and 425 gynephilic FtMs versus 599 female controls. Associations and interactions were investigated using binary logistic regression.

Results
Our data show that specific allele and genotype combinations of ERβ, ERα and AR are implicated in the genetic basis of transsexualism, and that MtF gender development requires AR, which must be accompanied by ERβ. An inverse allele interaction between ERβ and AR is characteristic of the MtF population: when either of these polymorphisms is short, the other is long. ERβ and ERα are also associated with transsexualism in the FtM population although there was no interaction between the polymorphisms. Our data show that ERβ plays a key role in the typical brain differentiation of humans.

Conclusion
ERβ plays a key role in human gender differentiation in males and females.		All trans subjects were homosexual wrt birth sex.Yesfull text
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The molecular mechanisms of sexual orientation and gender identityFisher, Ristori, Morelli, Maggia2018Molecular and Cellular Endocrinology4.10221164Differences between males and females are widely represented in nature. There are gender differences in phenotypes, personality traits, behaviors and interests, cognitive performance, and proneness to specific diseases. The most marked difference in humans is represented by sexual orientation and core gender identity, the origins of which are still controversial and far from being understood. Debates continue on whether sexual behavior and gender identity are a result of biological (nature) or cultural (nurture) factors, with biology possibly playing a major role. The main goal of this review is to summarize the studies available to date on the biological factors involved in the development of both sexual orientation and gender identity. A systematic search of published evidence was performed using Medline (from January 1948 to June 2017). Review of the relevant literature was based on authors’ expertise. Indeed, different studies have documented the possible role and interaction of neuroanatomic, hormonal and genetic factors. The sexual dimorphic brain is considered the anatomical substrate of psychosexual development, on which genes and gonadal hormones may have a shaping effect. In particular, growing evidence shows that prenatal and pubertal sex hormones permanently affect human behavior. In addition, heritability studies have demonstrated a role of genetic components. However, a convincing candidate gene has not been identified. Future studies (e.i. genome wide studies) are needed to better clarify the complex interaction between genes, anatomy and hormonal influences on psychosexual development.ReviewNofull text (via sci-hub)
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Biological origins of sexual orientation and gender identity: Impact on healthO'Hanlan, Gordon, Sullivan2018Gynecologic Oncology5.48214200Gynecologic Oncologists are sometimes consulted to care for patients who present with diverse gender identities or sexual orientations. Clinicians can create more helpful relationships with their patients if they understand the etiologies of these diverse expressions of sexual humanity. Multidisciplinary evidence reveals that a sexually dimorphic spectrum of somatic and neurologic anatomy, traits and abilities, including sexual orientation and gender identity, are conferred together during the first half of pregnancy due to genetics, epigenetics and the diversity of timing and function of sex chromosomes, sex-determining protein secretion, gonadal hormone secretion, receptor levels, adrenal function, maternally ingested dietary hormones, fetal health, and many other factors. Multiple layers of evidence confirm that sexual orientation and gender identity are as biological, innate and immutable as the other traits conferred during that critical time in gestation. Negative social responses to diverse orientations or gender identities have caused marginalization of these individuals with resultant alienation from medical care, reduced self-care and reduced access to medical care. The increased risks for many diseases, including gynecologic cancers are reviewed. Gynecologic Oncologists can potentially create more effective healthcare relationships with their patients if they have this information.Review. Evidence for both gender identity & sexuality being biologically innate, with quoted correspondence with prominent researchers.

The purpose of the article is to help practicioners better understand their trans and gay patients, so while it's quite thorough it's still a relatively accessible read.		Nofull text (via sci-hub)
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The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the TablePolderman, Kreukels, Irwig, Beach, Chan, Derks, Esteva, Ehrenfeld, Den Heijer, Posthuma, Raynor, Tishelman, Davis2018Behavior Genetics2.80552385The American Psychological Association defines gender identity as, “A person’s deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person’s sex assigned at birth or to a person’s primary or secondary sex characteristics” (American Psychological Association, Am Psychol 70(9):832–864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.Not a recommended source. Review of twin studies on "gender minorities" that measure things like personality traits and levels of masculinity and femininity, conflating deviance from gender stereotypes with transgenderism. Their definitions are skewed in a way that makes the results imply that ALL gender noncomformity stems from the same possible genetic basis as gender dysphoria and that personal attitudes about gender stereotypes are somehow biological in nature.Yesfull text
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Neurobiology of gender identity and sexual orientationRoselli2018Journal of Neuroendocrinology3.627421243Sexual identity and sexual orientation are independent components of a person's sexual identity. These dimensions are most often in harmony with each other and with an individual's genital sex, although not always. The present review discusses the relationship of sexual identity and sexual orientation to prenatal factors that act to shape the development of the brain and the expression of sexual behaviours in animals and humans. One major influence discussed relates to organisational effects that the early hormone environment exerts on both gender identity and sexual orientation. Evidence that gender identity and sexual orientation are masculinised by prenatal exposure to testosterone and feminised in it absence is drawn from basic research in animals, correlations of biometric indices of androgen exposure and studies of clinical conditions associated with disorders in sexual development. There are, however, important exceptions to this theory that have yet to be resolved. Family and twin studies indicate that genes play a role, although no specific candidate genes have been identified. Evidence that relates to the number of older brothers implicates maternal immune responses as a contributing factor for male sexual orientation. It remains speculative how these influences might relate to each other and interact with postnatal socialisation. Nonetheless, despite the many challenges to research in this area, existing empirical evidence makes it clear that there is a significant biological contribution to the development of an individual's sexual identity and sexual orientation.ReviewYesfull text
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Gender incongruence and the brain – Behavioral and neural correlates of voice gender perception in transgender peopleSmith, Junger, Pauly, Kellermann, Neulen, Neuschaefer-Rube, Derntl, Habel2018Hormones and Behavior3.587618The phenomenon of gender incongruence is hypothesized to arise from a discrepant sexual development of the brain and the genitals, contingent on genetic and hormonal mechanisms. We aimed at visualizing transgender identity on a neurobiological level, assuming a higher functional similarity to individuals of the aspired rather than assigned sex. Implementing a gender perception paradigm featuring male and female voice stimuli, behavioral and functional imaging data of transmen were compared to men and women, and to transwomen, respectively. Men had decreased activation in response to voices of the other sex in regions across the frontoparietal and insular cortex, while the activation patterns of women and transmen were characterized by little or no differentiation between male and female voices. Further, transmen had a comparatively high discrimination performance for ambiguous male voices, possibly reflecting a high sensitivity for voices of the aspired sex. Comparing transmen and transwomen yielded only few differences in the processing of male compared to female voices. In the insula, we observed a pattern similar to that of men and women, the neural responses of the transgender group being in accordance with their gender identity rather than assigned sex. Notwithstanding the similarities found dependent on biological sex, the findings support the hypothesis of gender incongruence being a condition in which neural processing modes are partly incongruent with one's assigned sex.Nofull text (via sci-hub)
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Grey and white matter volumes either in treatment-naïve or hormone-treated transgender women: a voxel-based morphometry studySpizzirri, Duran, Chaim-Avancini, Serpa, Cavallet, Pereira, Santos, Squarzoni, da Costa, Busatto, Abdo2018Scientific Reports4.37925554Many previous magnetic resonance imaging (MRI) studies have documented sex differences in brain morphology, but the patterns of sexual brain differences in transgender women – male sex assigned at birth – with a diagnosis of gender dysphoria (TW) have been rarely investigated to date. We acquired T1-weighted MRI data for the following four (n = 80) groups: treatment-naïve TW (TNTW), TW treated with cross-sex hormones for at least one year (TTW), cisgender men, and cisgender women (cisgender individuals as controls). Differences in whole-brain and regional white matter volume and grey matter volume (GMV) were assessed using voxel-based morphometry. We found lower global brain volumes and regional GMVs in a large portion of the posterior-superior frontal cortex in the cisgender women group than in the TTW and cisgender men groups. Additionally, both transgender groups exhibited lower bilateral insular GMVs than the cisgender women group. Our results highlight differences in the insula in both transgender groups; such differences may be characteristic of TW. Furthermore, these alterations in the insula could be related to the neural network of body perception and reflect the distress that accompanies gender dysphoria.Yesfull text
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Structural connections in the brain in relation to gender identity and sexual orientationBurke, Manzouri, Savic2017Scientific Reports4.37925575Both transgenderism and homosexuality are facets of human biology, believed to derive from different sexual differentiation of the brain. The two phenomena are, however, fundamentally unalike, despite an increased prevalence of homosexuality among transgender populations. Transgenderism is associated with strong feelings of incongruence between one’s physical sex and experienced gender, not reported in homosexual persons. The present study searches to find neural correlates for the respective conditions, using fractional anisotropy (FA) as a measure of white matter connections that has consistently shown sex differences. We compared FA in 40 transgender men (female birth-assigned sex) and 27 transgender women (male birth-assigned sex), with both homosexual (29 male, 30 female) and heterosexual (40 male, 40 female) cisgender controls. Previously reported sex differences in FA were reproduced in cis-heterosexual groups, but were not found among the cis-homosexual groups. After controlling for sexual orientation, the transgender groups showed sex-typical FA-values. The only exception was the right inferior fronto-occipital tract, connecting parietal and frontal brain areas that mediate own body perception. Our findings suggest that the neuroanatomical signature of transgenderism is related to brain areas processing the perception of self and body ownership, whereas homosexuality seems to be associated with less cerebral sexual differentiation.Controls for sexual orientation when reporting on the sex-atypicality of the measured FA-values in trans people, which eliminates some of the differences in trans & cis brains reported by previous studies. Nonetheless, the brain areas associated with self and body perception are still uniquely atypical in trans people, pointing to them as a likely source of gender dysphoria and identity.Yesfull text
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Altered White Matter and Sensory Response to Bodily Sensation in Female-to-Male Transgender IndividualsCase, Brang, Landazuri, Viswanathan, Ramachandran2017Archives of Sexual Behavior4.5072283While most people take identification with their body for granted, conditions such as phantom limb pain, alien hand syndrome, and xenomelia suggest that the feeling of bodily congruence is constructed and susceptible to alteration. Individuals with xenomelia typically experience one of their limbs as over-present and aversive, leading to a desire to amputate the limb. Similarly, many transgender individuals describe their untreated sexed body parts as incongruent and aversive, and many experience phantom body parts of the sex they identify with (Ramachandran, 2008). This experience may relate to differences in brain representation of the sexed body part, as suggested in xenomelia (McGeoch et al., 2011). We utilized magnetoencephalography imaging to record brain activity during somatosensory stimulation of the breast—a body part that feels incongruent to most presurgical female-to-male (FtM)-identified transgender individuals—and the hand, a body part that feels congruent. We measured the sensory evoked response in right hemisphere somatosensory and body-related brain areas and found significantly reduced activation in the supramarginal gyrus and secondary somatosensory cortex, but increased activation at the temporal pole for chest sensation in the FtM group (N = 8) relative to non-transgender females (N = 8). In addition, we found increased white matter coherence in the supramarginal gyrus and temporal pole and decreased white matter diffusivity in the anterior insula and temporal pole in the FtM group. These findings suggest that dysphoria related to gender-incongruent body parts in FtM individuals may be tied to differences in neural representation of the body and altered white matter connectivity.Studies bodily integration and sensation of the chest in trans men compared to controls. Brain activation patterns showed decreased integration and increased alarm in response to sensation on the chest in trans men with possible correllates to white matter structure. Sample was small but showed consistent results whether the men were taking T or not.

This study does not seem to have glaring issues or biases, but Case & Ramachandran have previously published a farcical study on bigenderism, and Ramachandran has been transphobic & dismissive of transgender brain research in the past, so I'd like to see these results reproduced by researchers with a better track record and with a higher sample size before using it as a source.		Nofull text (via sci-hub)
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Male‐to‐female gender dysphoria: Gender‐specific differences in resting‐state networksClemens, Junger, Pauly, Neulen, Neuschaefer‐Rube, Frölich, Mingoia, Derntl, Habel2017Brain and Behavior2.7081645Introduction
Recent research found gender‐related differences in resting‐state functional connectivity (rs‐FC) measured by functional magnetic resonance imaging (fMRI). To the best of our knowledge, there are no studies examining the differences in rs‐FC between men, women, and individuals who report a discrepancy between their anatomical sex and their gender identity, i.e. gender dysphoria (GD).

Methods
To address this important issue, we present the first fMRI study systematically investigating the differences in typical resting‐state networks (RSNs) and hormonal treatment effects in 26 male‐to‐female GD individuals (MtFs) compared with 19 men and 20 women.

Results
Differences between male and female control groups were found only in the auditory RSN, whereas differences between both control groups and MtFs were found in the auditory and fronto‐parietal RSNs, including both primary sensory areas (e.g. calcarine gyrus) and higher order cognitive areas such as the middle and posterior cingulate and dorsomedial prefrontal cortex. Overall, differences in MtFs compared with men and women were more pronounced before cross‐sex hormonal treatment. Interestingly, rs‐FC between MtFs and women did not differ significantly after treatment. When comparing hormonally untreated and treated MtFs, we found differences in connectivity of the calcarine gyrus and thalamus in the context of the auditory network, as well as the inferior frontal gyrus in context of the fronto‐parietal network.

Conclusion
Our results provide first evidence that MtFs exhibit patterns of rs‐FC which are different from both their assigned and their aspired gender, indicating an intermediate position between the two sexes. We suggest that the present study constitutes a starting point for future research designed to clarify whether the brains of individuals with GD are more similar to their assigned or their aspired gender.
Yesfull text
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Intrinsic network connectivity and own body perception in gender dysphoriaFeusner, Lidström, Moody, Dhejne, Bookheimer, Savic2017Brain Imaging And Behavior3.9783558Gender dysphoria (GD) is characterized by incongruence between one’s identity and gender assigned at birth. The biological mechanisms of GD are unclear. We investigated brain network connectivity patterns involved in own body perception in the context of self in GD. Twenty-seven female-to-male (FtM) individuals with GD, 27 male controls, and 27 female controls underwent resting state fMRI. We compared functional connections within intrinsic connectivity networks involved in self-referential processes and own body perception –default mode network (DMN) and salience network – and visual networks, using independent components analyses. Behavioral correlates of network connectivity were also tested using self-perception ratings while viewing own body images morphed to their sex assigned at birth, and to the sex of their gender identity. FtM exhibited decreased connectivity of anterior and posterior cingulate and precuneus within the DMN compared with controls. In FtM, higher “self” ratings for bodies morphed towards the sex of their gender identity were associated with greater connectivity of the anterior cingulate within the DMN, during long viewing times. In controls, higher ratings for bodies morphed towards their gender assigned at birth were associated with right insula connectivity within the salience network, during short viewing times. Within visual networks FtM showed weaker connectivity in occipital and temporal regions. Results suggest disconnectivity within networks involved in own body perception in the context of self in GD. Moreover, perception of bodies in relation to self may be reflective rather than reflexive, as a function of mesial prefrontal processes. These may represent neurobiological correlates to the subjective disconnection between perception of body and self-identification.Follow-up to Feusner, et al. 2016 "Female-to-Male Transsexual Individuals Demonstrate Different Own Body Identification", suggesting a neurological basis for trans men's identification with images of themselves as male.Nofull text (via sci-hub)
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Brain functional connectivity patterns in children and adolescents with gender dysphoria: Sex-atypical or not?Nota, Kreukels, den Heijer, Veltman, Cohen-Kettenis, Burke, Bakker2017Psychoneuroendocrinology4.90518138Various previous studies have reported that brains of people diagnosed with gender dysphoria (GD) show sex-atypical features. In addition, recent functional magnetic resonance imaging studies found that several brain resting-state networks (RSNs) in adults with GD show functional connectivity (FC) patterns that are not sex-atypical, but specific for GD. In the current study we examined whether FC patterns are also altered in prepubertal children and adolescents with GD in comparison with non-gender dysphoric peers. We investigated FC patterns within RSNs that were previously examined in adults: visual networks (VNs), sensorimotor networks (SMNs), default mode network (DMN) and salience network. Thirty-one children (18 birth assigned males; 13 birth assigned females) and 40 adolescents with GD (19 birth assigned males or transgirls; 21 birth assigned females or transboys), and 39 cisgender children (21 boys; 18 girls) and 41 cisgender adolescents (20 boys; 21 girls) participated. We used independent component analysis to obtain the network maps of interest and compared these across groups. Within one of the three VNs (VN-I), adolescent transgirls showed stronger FC in the right cerebellum compared with all other adolescent groups. Sex differences in FC between the cisgender adolescent groups were observed in the right supplementary motor area within one of the two SMNs (SMN-II; girls > boys) and the right posterior cingulate gyrus within the posterior DMN (boys > girls). Within these networks adolescent transgirls showed FC patterns similar to their experienced gender (female). Also adolescent transboys showed a FC pattern similar to their experienced gender (male), but within the SMN-II only. The prepubertal children did not show any group differences in FC, suggesting that these emerge with aging and during puberty. Our findings provide evidence for the existence of both GD-specific and sex-atypical FC patterns in adolescents with GD.Nofull text (via sci-hub)
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Genomic Characteristics of Gender Dysphoria Patients and Identification of Rare Mutations in RYR3 GeneYang, Zhu, Zhang, Sun, Ji, Ma, Xiao, Ding, Sun, Li2017Scientific Reports4.3791154Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.Pilot study with small sample size (13) and restricted to Han Chinese patients.Yesfull text
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Male-typical visuospatial functioning in gynephilic girls with gender dysphoria — organizational and activational effects of testosteroneBurke, Kreukels, Cohen-Kettenis, Veltman, Klink, Bakker2016Journal of Psychiatry & Neuroscience6.1862844Background: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT).

Methods: Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well.

Results: We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation.

Limitations: Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses.

Conclusion: Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.		Yesfull text
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Female-to-Male Transsexual Individuals Demonstrate Different Own Body IdentificationFeusner, Dervisic, Kosidou, Dhejne, Bookheimer, Savic2016Archives of Sexual Behavior4.5072634Transsexualism is characterized by feelings of incongruity between one’s natal sex and one’s gender identity. It is unclear whether transsexual individuals have a body image that is more congruent with their gender identity than their sex assigned at birth (natal sex) and, if so, whether there are contributions from perceptual dysfunctions. We compared 16 pre-hormone treatment female-to-male transsexual (FtM) individuals to 20 heterosexual female and 20 heterosexual male controls on a visual identification task. Participants viewed photographs of their own body that were morphed by different degrees to bodies of other females or males, and were instructed to rate “To what degree is this picture you?” We also tested global vs. local visual processing using the inverted faces task. FtM differed from both control groups in demonstrating higher self-identification ratings for bodies morphed to the sex congruent with their gender identity, and across a broad range of morph percentages. This difference was more pronounced for longer viewing durations. FtM showed reduced accuracy for upright faces compared with female controls for short duration stimuli, but no advantage for inverted faces. These results suggest different own body identification in FtM, consisting of a relatively diffuse identification with body images congruent with their gender identity. This is more likely accounted for by conscious, cognitive factors than perceptual differences.Demonstrates that trans men report a stronger sense of identification with images on themselves morphed to appear male. A more recent study by the same team (Feusner, et al. 2017 "Intrinsic network connectivity and own body perception in gender dysphoria") challenges this study's hypothesis that this is a conscious association rather than an innate one.Nofull text (via sci-hub)
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A Review of the Status of Brain Structure Research in TranssexualismGuillamon, Junque, Gómez-Gil2016Archives of Sexual Behavior4.50783638The present review focuses on the brain structure of male-to-female (MtF) and female-to-male (FtM) homosexual transsexuals before and after cross-sex hormone treatment as shown by in vivo neuroimaging techniques. Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females. These phenotypes have theoretical implications for brain intersexuality, asymmetry, and body perception in transsexuals as well as for Blanchard’s hypothesis on sexual orientation in homosexual MtFs. Falling within the aegis of the neurohormonal theory of sex differences, we hypothesize that cortical differences between homosexual MtFs and FtMs and male and female controls are due to differently timed cortical thinning in different regions for each group. Cross-sex hormone studies have reported marked effects of the treatment on MtF and FtM brains. Their results are used to discuss the early postmortem histological studies of the MtF brain.Review. Not recommended as a source. While functional as a summary of the research to date, it strains to summarize it in the context of Blanchard's transsexual typology.Yesfull text
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Neuroimaging studies in people with gender incongruenceKreukels, Guillamon2016International Review of Psychiatry4.1447273The current review gives an overview of brain studies in transgender people. First, we describe studies into the aetiology of feelings of gender incongruence, primarily addressing the sexual differentiation hypothesis: does the brain of transgender individuals resemble that of their natal sex, or that of their experienced gender? Findings from neuroimaging studies focusing on brain structure suggest that the brain phenotypes of trans women (MtF) and trans men (FtM) differ in various ways from control men and women with feminine, masculine, demasculinized and defeminized features. The brain phenotypes of people with feelings of gender incongruence may help us to figure out whether sex differentiation of the brain is atypical in these individuals, and shed light on gender identity development. Task-related imaging studies may show whether brain activation and task performance in transgender people is sex-atypical. Second, we review studies that evaluate the effects of cross-sex hormone treatment on the brain. This type of research provides knowledge on how changes in sex hormone levels may affect brain structure and function.ReviewYesfull text
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Kisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual OrientationTaziaux, Staphorsius, Ghatei, Bloom, Swaab, Bakker
2016The Journal of Clinical Endocrinology & Metabolism5.9582210Context:
Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex differences in kisspeptin expression have been shown in humans in adulthood, the developmental origin of this sex difference is unknown.

Objectives:
Our objectives were to determine the following: 1) when during development the sex difference in kisspeptin expression in the infundibular nucleus would emerge and 2) whether this sex difference is related to sexual orientation or transsexuality.

Design and Setting:
Postmortem hypothalamic tissues were collected by The Netherlands Brain Bank, and sections were stained for kisspeptin by immunohistochemistry.

Patients:
Hypothalami of 43 control subjects were categorized into three periods: infant/prepubertal (six girls, seven boys), adult (11 women, seven men), and elderly (six aged women, six aged men). Eight male-to-female (MTF) transsexuals, three HIV+ heterosexual men, and five HIV+ homosexual men were also analyzed.

Main Outcome Measure:
We estimated the total number of kisspeptin-immunoreactive neurons within the infundibular nucleus.

Results:
Quantitative analysis confirmed that the human infundibular kisspeptin system exhibits a female-dominant sex difference. The number of kisspeptin neurons is significantly greater in the infant/prepubertal and elderly periods compared with the adult period. Finally, in MTF transsexuals, but not homosexual men, a female-typical kisspeptin expression was observed.

Conclusions:
These findings suggest that infundibular kisspeptin neurons are sensitive to circulating sex steroid hormones throughout life and that the sex reversal observed in MTF transsexuals might reflect, at least partially, an atypical brain sexual differentiation.		Female-like kisspeptin expression occurs in the brains of trans women and not in homosexual cis men, suggesting its role in the sex differentiation of the brain and providing further evidence that trans women have female-like neurologyYesfull text
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The CYP17 MspA1 Polymorphism and the Gender DysphoriaFernández, Cortés-Cortés, Esteva, Gómez-Gil, Almaraz, Lema, Rumbo, Haro-Mora, Roda, Guillamón, Pásaro2015The Journal of Sexual Medicine3.8022522Introduction
The A2 allele of the CYP17 MspA1 polymorphism has been linked to higher levels of serum testosterone, progesterone, and estradiol.

Aim
To determine whether the CYP17 MspA1 polymorphism is associated with transsexualism.

Methods
We analyzed 151 male-to-female (MtF), 142 female-to-male (FtM), 167 control male, and 168 control female individuals. Fragments that included the mutation were amplified by PCR and digested with MspA1. Our data were compared with the allele/genotype frequencies provided by the 1000 Genomes Data Base, and contrasted with a MEDLINE search of the CYP17 MspA1 polymorphism in the literature.

Main Outcome Measures
We investigated the association between transsexualism and the CYP17 MspA1 polymorphism.

Results
A2 frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887). This observation concurred with the 1000 Genomes Data Base and the MEDLINE search.

Conclusion
Our data confirm a sex-dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM > MtF, suggestive of a hypothetical A2 involvement in transsexualism since the allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex.		Nofull text (via sci-hub)
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Structural Connectivity Networks of Transgender PeopleHahn, Kranz, Küblböck, Kaufmann, Ganger, Hummer, Seiger, Spies, Winkler, Kasper, Windischberger, Swaab, Lanzenberger2015Cerebral Cortex5.04362262Although previous investigations of transsexual people have focused on regional brain alterations, evaluations on a network level, especially those structural in nature, are largely missing. Therefore, we investigated the structural connectome of 23 female-to-male (FtM) and 21 male-to-female (MtF) transgender patients before hormone therapy as compared with 25 female and 25 male healthy controls. Graph theoretical analysis of whole-brain probabilistic tractography networks (adjusted for differences in intracranial volume) showed decreased hemispheric connectivity ratios of subcortical/limbic areas for both transgender groups. Subsequent analysis revealed that this finding was driven by increased interhemispheric lobar connectivity weights (LCWs) in MtF transsexuals and decreased intrahemispheric LCWs in FtM patients. This was further reflected on a regional level, where the MtF group showed mostly increased local efficiencies and FtM patients decreased values. Importantly, these parameters separated each patient group from the remaining subjects for the majority of significant findings. This work complements previously established regional alterations with important findings of structural connectivity. Specifically, our data suggest that network parameters may reflect unique characteristics of transgender patients, whereas local physiological aspects have been shown to represent the transition from the biological sex to the actual gender identity.Yesfull text
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Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain.Hoekzema, Schagen, Kreukels, Veltman, Cohen-Kettenis, Delemarre-van de Waal, Bakker2015Psychoneuroendocrinology4.9055633The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.Nofull text (via sci-hub)
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Anatomical and Functional Findings in Female-to-Male Transsexuals: Testing a New Hypothesis.Manzouri, Kosidou, Savic2015Cerebral Cortex5.0435035Gender dysphoria (GD) is characterized by incongruence between onés gender assigned at birth and the gender that one identifies with. The biological mechanisms of GD are unclear, especially in female-to-male transsexuals (FtM-TR). Here, we investigate whether distinct structural and functional patterns along cerebral midline networks processing own-body perception may constitute a biological correlate. Method: MRI of functional connectivity, cortical thickness, surface area, and gray matter volume was carried out in 28 female-to-male transsexuals (FtM-TR) and 68 cis-sexual controls (34 male). FtM-TR displayed thicker mid-frontal, precuneal-parietal, and lingual cortex than both male and female controls, whereas, in regions with reported anatomical sex differences among the controls, FtM-TR followed patterns of the gender assigned at their birth. FtM-TR also displayed weaker functional connections from the pregenual anterior cingulate to the insular cortex, and the temporo parietal junction compared with both control groups. Distinct structural and functional pattern in the own-body image network may represent biological markers for the dysphoric own-body perception in transgender individuals.Not a recommended source. Comes to the conclusion that brains areas involved in self-perception are likely involved in transgenderism, but is often used by gender-critical folks anyway because it reports that various brain areas in trans men are still fundamentally similar to those of cis women. The study is limited in that it only involved homosexual (wrt birth sex) FtMs tested against cisgender heterosexual controls, and its findings conflict with other research on the subject. A more recent study by the same authors (Burke, et al. 2017 "Structural connections in the brain in relation to gender identity and sexual orientation") has stronger data and comes to a stronger conclusion.Yesfull text
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Evidence supporting the biologic nature of gender identity.Sarasawat, Weinand, Safer2015Endocrine Practice3.44373328OBJECTIVE: To review current literature that supports a biologic basis of gender identity.

METHODS: A traditional literature review.

RESULTS: Evidence that there is a biologic basis for gender identity primarily involves (1) data on gender identity in patients with disorders of sex development (DSDs, also known as differences of sex development) along with (2) neuroanatomical differences associated with gender identity.

CONCLUSIONS: Although the mechanisms remain to be determined, there is strong support in the literature for a biologic basis of gender identity.		Review of research done on both intersex and transgender people supporting a biological basis for gender identity.Nofull text (via sci-hub)
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The transsexual brain – A review of findings on the neural basis of transsexualismSmith, Junger, Derntl, Habel2015Neuroscience & Biobehavioral Reviews8.9898697Transsexualism describes the condition when a person's psychological gender differs from his or her biological sex and is commonly thought to arise from a discrepant cerebral and genital sexual differentiation. This review intends to give an extensive overview of structural and functional neurobiological correlates of transsexualism and their course under cross-sex hormonal treatment. Research in this field enables insight into the stability or variability of gender differences and their relation to hormonal status. For a number of sexually dimorphic brain structures or processes, signs of feminisation or masculinisation are observable in transsexual individuals, which, during hormonal treatment, partly seem to further adjust to characteristics of the desired sex. Still, it appears the data are quite inhomogeneous, mostly not replicated and in many cases available for male-to-female transsexuals only. As the prevalence of homosexuality is markedly higher among transsexuals than among the general population, disentangling correlates of sexual orientation and gender identity is a major problem. To resolve such deficiencies, the implementation of specific research standards is proposed.ReviewNofull text (via sci-hub)
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Hypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescentsBurke, Cohen-Kettenis, Veltman, Klink, Bakker2014Frontiers in Endocrinology5.55562185The 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.Yesfull text
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Click-Evoked Otoacoustic Emissions in Children and Adolescents with Gender Identity DisorderBurke, Menks, Cohen-Kettenis, Klink, Bakker2014Archives of Sexual Behavior4.507187Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and neonates already show a similar sex difference in CEOAEs. Weaker responses in males are proposed to originate from elevated levels of testosterone during perinatal sexual differentiation. Therefore, CEOAEs may be used as a retrospective indicator of someone’s perinatal androgen environment. Individuals diagnosed with Gender Identity Disorder (GID), according to DSM-IV-TR, are characterized by a strong identification with the other gender and discomfort about their natal sex. Although the etiology of GID is far from established, it is hypothesized that atypical levels of sex steroids during a critical period of sexual differentiation of the brain might play a role. In the present study, we compared CEOAEs in treatment-naïve children and adolescents with early-onset GID (24 natal boys, 23 natal girls) and control subjects (65 boys, 62 girls). We replicated the sex difference in CEOAE response amplitude in the control group. This sex difference, however, was not present in the GID groups. Boys with GID showed stronger, more female-typical CEOAEs whereas girls with GID did not differ in emission strength compared to control girls. Based on the assumption that CEOAE amplitude can be seen as an index of relative androgen exposure, our results provide some evidence for the idea that boys with GID may have been exposed to lower amounts of androgen during early development in comparison to control boys.Not a recommended source. Followed up in Burke, et al., 2020, "Postnatal Effects of Sex Hormones on Click-Evoked Otoacoustic Emissions: A Study of Adolescents with Gender Dysphoria", which suggests CEOAEs are affected by HRT and may not be a reliable marker for innate GD.Nofull text (via sci-hub)
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More than Just Two Sexes: The Neural Correlates of Voice Gender Perception in Gender DysphoriaJunger, Habel, Bröhr, Neulen, Neuschaefer-Rube, Birkholz, Kohler, Schneider, Derntl, Pauly2014PLOS One3.243065Gender 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.Yesfull text
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Neural mechanisms underlying sexual arousal in connection with sexual hormone levels: a comparative study of the postoperative male-to-female transsexuals and premenopausal and menopausal women.Kim, Jeong2014Neuroreport1.837114This study compared the brain activation patterns associated with visual sexual arousal in connection with sexual hormone levels in postoperative male-to-female (MTF) transsexuals and normal premenopausal and menopausal women using 3.0 T functional MRI. A total of 30 volunteers including 10 premenopausal women, 10 menopausal women, and 10 postoperative MTF transsexuals who had undergone sex reassignment surgery participated in this study. Brain activity was measured while viewing erotic male and female nude pictures. The free testosterone and estradiol levels of the postoperative MTF transsexuals were not in the normal range seen in normal premenopausal women, but were in range seen in menopausal women. The postoperative MTF transsexuals showed significantly higher activities in the hippocampus, parahippocampal gyrus, amygdala, putamen, globus pallidus, thalamus, and head of caudate nucleus in response to erotic male nude pictures in contrast to female pictures (P<0.005). The predominant activation areas observed in the postoperative MTF transsexuals in contrast to the menopausal women when viewing male nude pictures included the insula, hippocampus, thalamus, and putamen (P<0.005). Similar to the postoperative MTF transsexuals, the premenopausal women showed significantly higher activities than menopausal women in the insula, hippocampus, thalamus, and parahippocampal gyrus (P<0.005). This study revealed that the brain activation patterns associated with visual sexual arousal in postoperative MTF transsexuals are similar to those in premenopausal women, although the sexual hormone levels in the postoperative MTF transsexuals are in the average range of those in menopausal women.Nofull text (via sci-hub)
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Cerebral serotonin transporter asymmetry in females, males and male-to-female transsexuals measured by PET in vivo.Kranz, Hahn, Baldinger, Haeusler, Philippe, Kaufmann, Wadsak, Savli, Hoeflich, Kraus, Vanicek, Mitterhauser, Kasper, Lanzenberger2014Brain Structure and Function4.093313The 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.Nofull text (via sci-hub)
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White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging.Kranz, Hahn, Kaufmann, Küblböck, Hummer, Ganger, Seiger, Winkler, Swaab, Windischberger, Kasper, Lanzenberger2014The Journal of Neuroscience6.16795313Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.Yesfull text
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Neural Network of Body Representation Differs between Transsexuals and CissexualsLin, Ku, Chao, Tu, Li, Cheng, Su, Lee, Hsieh2014PLOS One3.244626Body image is the internal representation of an individual’s own physical appearance. Individuals with gender identity disorder (GID), commonly referred to as transsexuals (TXs), are unable to form a satisfactory body image due to the dissonance between their biological sex and gender identity. We reasoned that changes in the resting-state functional connectivity (rsFC) network would neurologically reflect such experiential incongruence in TXs. Using graph theory-based network analysis, we investigated the regional changes of the degree centrality of the rsFC network. The degree centrality is an index of the functional importance of a node in a neural network. We hypothesized that three key regions of the body representation network, i.e., the primary somatosensory cortex, the superior parietal lobule and the insula, would show a higher degree centrality in TXs. Twenty-three pre-treatment TXs (11 male-to-female and 12 female-to-male TXs) as one psychosocial group and 23 age-matched healthy cissexual control subjects (CISs, 11 males and 12 females) were recruited. Resting-state functional magnetic resonance imaging was performed, and binarized rsFC networks were constructed. The TXs demonstrated a significantly higher degree centrality in the bilateral superior parietal lobule and the primary somatosensory cortex. In addition, the connectivity between the right insula and the bilateral primary somatosensory cortices was negatively correlated with the selfness rating of their desired genders. These data indicate that the key components of body representation manifest in TXs as critical function hubs in the rsFC network. The negative association may imply a coping mechanism that dissociates bodily emotion from body image. The changes in the functional connectome may serve as representational markers for the dysphoric bodily self of TXs.Yesfull text
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Brain Signature Characterizing the Body-Brain-Mind Axis of TranssexualsKu, Lin, Chao, Tu, Li, Cheng, Su, Lee, Hsieh2013PLOS One3.242778Individuals 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.Yesfull text
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Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls—A Voxel Based Morphometry StudySimon, Kozák, Simon, Czobor, Unoka, Szabó, Csukly2013PLOS One3.2461197Gender 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.Yesfull text
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Sex differences in verbal fluency during adolescence: a functional magnetic resonance imaging study in gender dysphoric and control boys and girls.Soleman, Schagen, Veltman, Kreukels, Cohen-Kettenis, Lambalk, Wouters, Delemarre-van de Waal2013The Journal of Sexual Medicine3.802377INTRODUCTION: In the literature, verbal fluency (VF) is generally described as a female-favoring task. Although it is conceivable that this sex difference only evolves during adolescence or adulthood under influence of sex steroids, this has never been investigated in young adolescents.

AIM: First, to assess sex differences in VF performance and regional brain activation in adolescents. Second, to determine if untreated transsexual adolescents differ from their sex of birth with regard to VF performance and regional brain activation.

METHOD: Twenty-five boys, 26 girls, 8 Male-to-Female transsexual adolescents (MtFs), and 14 Female-to-Male transsexual adolescents (FtMs) were tested in a cross-sectional study, while performing a phonetic and semantic VF task within an MRI scanner.

MAIN OUTCOME MEASURES: Functional MRI response during VF task.

RESULTS: Boys and girls produced similar amounts of words, but the group MtFs produced significantly more words in the phonetic condition compared to control boys, girls, and FtMs. During the semantic condition, no differences were found. With regard to brain activity, control boys showed more activation in the right Rolandic operculum, a small area adjacent to Broca's area, compared to girls. No significant differences in brain activity were found comparing transsexual adolescents, although sub-threshold activation was found in the right Rolandic operculum indicating a trendwise increase in activation from control girls to FtMs to MtFs to control boys.

CONCLUSIONS: The better performance of MtFs is consistent with our expectation that MtFs perform better on female-favoring tasks. Moreover, they produced more words than girls and FtMs. Even though a trendwise linear increase in brain activity between the four groups only approached significance, it may indicate differences in individuals with gender identity disorder compared to their birth sex. Although our findings should thus be interpreted with caution, they suggest a biological basis for both transgender groups performing in-between the two sexes.		Nofull text (via sci-hub)
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Cortical Thickness in Untreated TranssexualsZubiaurre-Elorza, Junque, Gómez-Gil, Segovia, Carrillo, Rametti, Guillamon
2013Cerebral Cortex5.04392107Sex 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.All subjects were homosexual wrt natal sex.Yesfull text
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Increased Cortical Thickness in Male-to-Female Transsexualism.Luders, Sánchez, Tosun, Shattuck, Gaser, Vilain, Toga2012Journal of Behavioral and Brain ScienceN/A9143Background
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.		Does not control for sexual orientation.Yesfull text
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Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study.Rametti, Carrillo, Gómez-Gil, Junque, Zubiaurre-Elorza, Segovia, Gomez, Karadi, Guillamon2012Psychoneuroendocrinology4.905752Diffusion tensor imaging (DTI) can sensitively detect white matter sex differences and the effects of pharmacological treatments. Before cross-sex hormone treatment, the white matter microstructure of several brain bundles in female-to-male transsexuals (FtMs) differs from those in females but not from that in males. The purpose of this study was to investigate whether cross-sex hormone treatment (androgenization) affects the brain white matter microstructure. Using a Siemens 3 T Trio Tim Magneton, DTI was performed twice, before and during cross-sex hormonal treatment with testosterone in 15 FtMs scanned. Fractional anisotropy (FA) was analyzed on white matter of the whole brain, and the latter was spatially analyzed using Tract-Based Spatial Statistics. Before each scan the subjects were assessed for serum testosterone, sex hormone binding globulin level (SHBG), and their free testosterone index. After at least seven months of cross-gender hormonal treatment, FA values increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) in FtMs compared to their pre-treatment values. Hierarchical regression analyses showed that the increments in the FA values in the SLF and CST are predicted by the free testosterone index before hormonal treatment. All these observations suggest that testosterone treatment changes white matter microstructure in FtMs.Nofull text (via sci-hub)
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Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disordersBao, Swaab2011Frontiers in Neuroendocrinology8.106371460During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual’s perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one’s postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.

Research highlights
► Gender identity and sexual orientation are permanently programmed in the fetal brain.
► Testosterone in the fetal stage determines sexual differentiation of the human brain.
► The degree of genital masculinization does not necessarily reflect that of the brain.
► No evidence indicates social environment affect gender identity or sexual orientation.
► Sex differences in the brain determine sex-specific prevalence of brain disorders.		Review. The abstract provides a very helpful and concise explanation of how sexual differentiation of the brain happens and how it's possible for the brain and body to have differing levels of masculinization.

"No evidence indicates social environment affect gender identity or sexual orientation."		Nofull text (via sci-hub)
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White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging studyRametti, Carrillo, Gómez-Gil, Junque, Segovia, Gomez, Guillamon2011Journal of Psychiatric Research4.791212828Background
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.		Nofull text (via sci-hub)
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The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI studyRametti, Carrillo, Gómez-Gil, Junque, Zubiarre-Elorza, Segovia, Gomez, Guillamon2011Journal of Psychiatric Research4.791121299Background
Diffusion tensor imaging (DTI) has been shown to be sensitive in detecting white matter differences between sexes. Before cross-sex hormone treatment female to male transsexuals (FtM) differ from females but not from males in several brain fibers. The purpose of this paper is to investigate whether white matter patterns in male to female (MtF) transsexuals before commencing cross-sex hormone treatment are also more similar to those of their biological sex or whether they are more similar to those of their gender identity.

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

Results
MtF transsexuals differed from both male and female controls bilaterally in the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract.

Conclusions
Our results show that the white matter microstructure pattern in untreated MtF transsexuals falls halfway between the pattern of male and female controls. The nature of these differences suggests that some fasciculi do not complete the masculinization process in MtF transsexuals during brain development.		Nofull text (via sci-hub)
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Sex Dimorphism of the Brain in Male-to-Female TranssexualsSavic, Arver2011Cerebral Cortex5.043146170Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus.The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.Yesfull text
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Sexual differentiation of the human brain in relation to gender identity and sexual orientationSavic, Garcia-Falgueras, Swaab2010Progress in Brain Research2.207167196It is believed that during the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. According to this concept, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation should be programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no proof that social environment after birth has an effect on gender identity or sexual orientation. Data on genetic and hormone independent influence on gender identity are presently divergent and do not provide convincing information about the underlying etiology. To what extent fetal programming may determine sexual orientation is also a matter of discussion. A number of studies show patterns of sex atypical cerebral dimorphism in homosexual subjects. Although the crucial question, namely how such complex functions as sexual orientation and identity are processed in the brain remains unanswered, emerging data point at a key role of specific neuronal circuits involving the hypothalamus.Review. The abstract provides a very helpful and concise explanation of how sexual differentiation of the brain happens and how it's possible for the brain and body to have differing levels of masculinization.

"There is no proof that social environment after birth has an effect on gender identity or sexual orientation."		Nofull text (via sci-hub)
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Neuroimaging differences in spatial cognition between men and male-to-female transsexuals before and during hormone therapy.Schöning, Engelien, Bauer, Kugel, Kersting, Roestel, Zwitserlood, Pyka, Dannlowski, Lehmann, Heindel, Arolt, Konrad2010The Journal of Sexual Medicine3.80288138INTRODUCTION: Neuropsychological abnormalities in transsexual patients have been reported in comparison with subjects without gender identity disorder (GID), suggesting differences in underlying neurobiological processes. However, these results have not consistently been confirmed. Furthermore, studies on cognitive effects of cross-sex hormone therapy also yield heterogeneous results.

AIM: We hypothesized that untreated transsexual patients differ from men without GID in activation pattern associated with a mental rotation task and that these differences may further increase after commencing of hormonal treatment.

METHOD: The present study investigated 11 male-to-female transsexual (MFTS) patients prior to cross-sex hormone therapy and 11 MFTS patients during hormone therapy in comparison with healthy men without GID. Using functional magnetic resonance imaging at 3-Tesla, a mental rotation paradigm with proven sexual dimorphism was applied to all subjects. Data were analyzed with SPM5.

MAIN OUTCOME MEASURES: Patterns of brain activation associated with a mental rotation task.

RESULTS: The classical mental rotation network was activated in all three groups, but significant differences within this network were observed. Men without GID exhibited significantly greater activation of the left parietal cortex (BA 40), a key region for mental rotation processes. Both transsexual groups revealed stronger activation of temporo-occipital regions in comparison with men without GID.

CONCLUSIONS: Our results confirmed previously reported deviances of brain activation patterns in transsexual men from men without GID and also corroborated these findings in a group of transsexual patients receiving cross-sex hormone therapy. The present study indicates that there are a priori differences between men and transsexual patients caused by different neurobiological processes or task-solving strategies and that these differences remain stable over the course of hormonal treatment.		Nofull text (via sci-hub)
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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.Gizewski, Krause, Schlamann, Happich, Ladd, Forsting, Senf2009The Journal of Sexual Medicine3.80295127INTRODUCTION: 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.		Nofull text (via sci-hub)
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Androgen Receptor Repeat Length Polymorphism Associated with Male-to-Female TranssexualismHare, Bernard, Sánchez, Baird, Vilain, Kennedy, Harley2009Biological Psychiatry13.38233298Background
There is a likely genetic component to transsexualism, and genes involved in sex steroidogenesis are good candidates. We explored the specific hypothesis that male-to-female transsexualism is associated with gene variants responsible for undermasculinization and/or feminization. Specifically, we assessed the role of disease-associated repeat length polymorphisms in the androgen receptor (AR), estrogen receptor β (ERβ), and aromatase (CYP19) genes.

Methods
Subject-control analysis included 112 male-to-female transsexuals and 258 non-transsexual males. Associations and interactions were investigated between CAG repeat length in the AR gene, CA repeat length in the ERβ gene, and TTTA repeat length in the CYP19 gene and male-to-female transsexualism.

Results
A significant association was identified between transsexualism and the AR allele, with transsexuals having longer AR repeat lengths than non-transsexual male control subjects (p = .04). No associations for transsexualism were evident in repeat lengths for CYP19 or ERβ genes. Individuals were then classified as short or long for each gene polymorphism on the basis of control median polymorphism lengths in order to further elucidate possible combined effects. No interaction associations between the three genes and transsexualism were identified.

Conclusions
This study provides evidence that male gender identity might be partly mediated through the androgen receptor.		Yesfull text
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Regional gray matter variation in male-to-female transsexualismLuders, Sánchez, Gaser, Toga, Narr, Hamilton, Vilain2009NeuroImage6.556144416Gender identity—one's sense of being a man or a woman—is a fundamental perception experienced by all individuals that extends beyond biological sex. Yet, what contributes to our sense of gender remains uncertain. Since individuals who identify as transsexual report strong feelings of being the opposite sex and a belief that their sexual characteristics do not reflect their true gender, they constitute an invaluable model to understand the biological underpinnings of gender identity. We analyzed MRI data of 24 male-to-female (MTF) transsexuals not yet treated with cross-sex hormones in order to determine whether gray matter volumes in MTF transsexuals more closely resemble people who share their biological sex (30 control men), or people who share their gender identity (30 control women). Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men. These findings provide new evidence that transsexualism is associated with distinct cerebral pattern, which supports the assumption that brain anatomy plays a role in gender identity.Yesfull text
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A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualismBentz, Hefler, Kaufmann, Huber, Kolbus, Tempfer2008Fertility and Sterility7.329131148Objective
To assess the association between transsexualism and allele and genotype frequencies of the common cytochrome P450 (CYP) 17 −34 T>C single nucleotide polymorphism (SNP).

Design
Case-control study.

Setting
Academic research institution.

Patient(s)
102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls.

Intervention(s)
Buccal swabs and multiplex polymerase chain reaction on a microarray system.

Main Outcome Measure(s)
Analysis of the CYP17 −34 T>C SNP.

Result(s)
CYP17 −34 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 55/98 [56%] and CYP17 C: 43/98 [44%] versus CYP17 T: 1253/1826 [69%] and CYP17 C: 573/1826 [31%], respectively). In accordance, genotype distributions were also different between FtM transsexuals and female controls using a recessive genotype model (CYP17 T/T+T/C: 39/49 [80%] and C/C 10/49 [20%] vs. CYP17 T/T+T/C: 821/913 [90%] and C/C 92/913 [10%], respectively). The CYP17 −34 T>C allele and genotype distributions were not statistically significantly different between MtF transsexuals and male controls. Of note, the CYP17 −34 T>C allele distribution was gender-specific among controls (CYP17 C: males; 604 of 1512 [40%] vs. females; 573 of 1826 [31%]). The MtF transsexuals had an allele distribution equivalent to male controls, whereas FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls.

Conclusion(s)
These data support CYP17 as a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T −34C allele distribution pattern is associated with FtM transsexualism.		Yesfull text
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A sex difference in the hypothalamic uncinate nucleus: relationship to gender identityGarcia-Falgueras, Swaab2008Brain13.5254546Transsexuality 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.Yesfull text
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Male-to-Female Transsexuals Show Sex-Atypical Hypothalamus Activation When Smelling Odorous SteroidsBerglund, Lindström, Dhejne-Helmy, Savic2007Cerebral Cortex5.043162187One 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.Shows fundamental similarities in the brain function of trans women to cis women, though they occupy an intermediate range between cis males and females. Subjects were nonhomosexual (wrt birth sex) and had no history of hormone treatment, so the results cannot be better explained by sexual orientation or exposure to post-natal hormones.Yesfull text
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Sexual differentiation of the brain and behaviorSwaab2007Best Practice & Research: Clinical Endocrinology & Metabolism4.6929278During the intrauterine period the human brain develops in the male direction via direct action of a boy's testosterone, and in the female direction through the absence of this hormone in a girl. During this time, gender identity (the feeling of being a man or a woman), sexual orientation, and other behaviors are programmed. As sexual differentiation of the genitals takes places in the first 2 months of pregnancy, and sexual differentiation of the brain starts during the second half of pregnancy, these two processes may be influenced independently of each other, resulting in transsexuality. This also means that in the case of an ambiguous gender at birth, the degree of masculinization of the genitals may not reflect the same degree of masculinization of the brain. Differences in brain structures and brain functions have been found that are related to sexual orientation and gender.Nofull text (via sci-hub)
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Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structureHulshoff Pol, Cohen-Kettenis, Van Haren, Peper, Brans, Cahn, Schnack, Gooren, Kahn2006European Journal of Endocrinology6.664159126Objective: 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.		Yesfull text
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Sex steroid-related genes and male-to-female transsexualismHenningsson, Westberg, Nilsson, Lundström, Ekselius, Bodlund, Lindström, Hellstrand, Rosmond, Eriksson, Landén2005Psychoneuroendocrinology4.90517843Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and—after aromatase-catalyzed conversion to estradiol—via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERβ gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.Nofull text (via sci-hub)
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Callosal Shapes at the Midsagittal Plane: MRI Differences of Normal Males, Normal Females, and GIDYokota, Kawamura, Kameya2005Conference proceedings Annual International Conference of the IEEE Engineering in Medicine and Biology SocietyN/A42124We 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.Findings presented at the Annual International Conference of the IEEE Engineering in Medicine and Biology Society 2005 and not published in a journal.Nofull text (via sci-hub)
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Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation.Swaab2004Gynecological Endocrinology2.2615779Male sexual differentiation of the brain and behavior are thought, on the basis of experiments in rodents, to be caused by androgens, following conversion to estrogens. However, observations in human subjects with genetic and other disorders show that direct effects of testosterone on the developing fetal brain are of major importance for the development of male gender identity and male heterosexual orientation. Solid evidence for the importance of postnatal social factors is lacking. In the human brain, structural diferences have been described that seem to be related to gender identity and sexual orientation.ReviewNofull text (via sci-hub)
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Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic NucleusKruijver, Zhou, Pool, Hofman, Gooren, Swaab2000The Journal of Clinical Endocrinology & Metabolism5.958603763Transsexuals 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.Yesfull text
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A sex difference in the human brain and its relation to transsexualityZhou, Hofman, Gooren, Swaab1995Nature49.961001813TRANSSEXUALS 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.Significant as one of the first and best-known studies on trans brains that demonstrate neurological similarities to their experienced gender. Not a recommended source on its own, as the sample size is extremely small (6 MTF subjects) and the results are better explored and built from in more recent studies.Nofull text (via sci-hub)
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