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The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study
Abstract
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.
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.
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.
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.
... MRI studies show that ICV in adult (Rametti et al., 2011b) and adolescent (Hoekzema et al., 2015) untreated homosexual MtFs is similar to male controls'. Moreover, GM, WM, and CSF volumes in homosexual MtFs do not differ from those of control males and are significantly greater than those of control females (Table 4). ...
... Recently, white matter microstructure has been studied in early-onset homosexual MtFs using DTI (Table 5; Fig. 3a). There are sex differences in FA, males showing greater FA values in important brain fascicles such as the right and left superior longitudinal fasciculi (rSLF; lSLF), the inferior frontooccipital fasciculus (IFOF), the cingulum (Cin), the forceps minor (Fm), and the corticospinal tract (CST) (Rametti et al., 2011b). Interestingly, early-onset homosexual MtFs show demasculinized FA in all these brain fascicles because their FA values were statistically different from the values for both the male and female control groups. ...
... In regard to white matter microstructure, the study of Kranz et al. (2014) mixed sexual orientation within their MtF, FtM, and female and male control groups ( Table 7). The differences in design and sampling make it almost impossible to compare these studies with those of our group (Rametti et al., 2011a(Rametti et al., , 2011b; see Tables 5, 6, 7). However, since in Kranz et al.'s study most of the FtMs were homosexuals (19/24), it could feasibly be compared with the results of Rametti et al. (2011a) presented in the previous section (Table 6). ...
Transgender men and women represent about 0.6 -1.1%% of the general population. Gender affirming hormone therapy (GAHT) helps ameliorate gender dysphoria and promote well-being. However, these treatments’ cardiovascular (CV) effects are difficult to evaluate due to the limited number of extensive longitudinal studies focused on CV outcomes in this population. Furthermore, these studies are mainly observational and difficult to interpret due to a variety of hormone regimens and observation periods, together with possible bias by confounding factors (comorbidities, estrogen types, smoking, alcohol abuse, HIV infection). In addition, the introduction of GAHT at increasingly earlier ages, even before the full development of the secondary sexual characteristics, could lead to long-term changes in CV risk compared to current data.
This review examines the impact of GAHT in the transgender population on CV outcomes and surrogate markers of CV health. Furthermore, we review available data on changes in DNA methylation or RNA transcription induced by GAHT that may translate into changes in metabolic parameters that could increase CV risk.
... Por otra parte, los estudios de Rametti y colaboradores (Rametti et al., 2011a(Rametti et al., , 2011b(Rametti et al., , 2012 utilizaron imágenes de tensor de difusión (IDT) para evaluar la anisotropía fraccionada (FA) de los tractos de fibra de materia blanca en la población transexual y control. Cuando se examinó al grupo MtF y a los controles masculinos y femeninos, se encontró que la microestructura de la materia blanca de la población MtF difería de los controles en casi todos los fascículos del cerebro (fascículos longitudinales superiores, fascículo frontooccipital inferior, cíngulo, fórceps menor y tracto corticoespinal) encontrándose en un punto intermedio entre ambos grupos (hombres y mujeres control). ...
... MtF. En el caso de las personas FtM el patrón de microestructura de la materia blanca fue más cercano al de los hombres, mostrando valores de FA más altos que el grupo control femenino en varias regiones del cerebro (fascículo longitudinal superior, el fórceps menor y el tracto corticoespinal, entre otros) (Rametti et al., 2011a(Rametti et al., , 2011b. En general estos estudios muestran un patrón de microestructura estadísticamente diferente al del sexo cromosómico, es decir, desmasculinizado en la población MtF y masculinizado en FtM (Kranz et al., 2014b;Rametti et al., 2011a). ...
... MtF. En el caso de las personas FtM el patrón de microestructura de la materia blanca fue más cercano al de los hombres, mostrando valores de FA más altos que el grupo control femenino en varias regiones del cerebro (fascículo longitudinal superior, el fórceps menor y el tracto corticoespinal, entre otros) (Rametti et al., 2011a(Rametti et al., , 2011b. En general estos estudios muestran un patrón de microestructura estadísticamente diferente al del sexo cromosómico, es decir, desmasculinizado en la población MtF y masculinizado en FtM (Kranz et al., 2014b;Rametti et al., 2011a). ...
La transexualidad se caracteriza por una marcada incongruencia entre género y sexo biológico. La población transexual busca la transición “hombre-mujer” (MtF) o “mujerhombre”(FtM). La literatura muestra una mayor concordancia entre gemelos monocigóticos que dicigóticos, lo que sugiere la contribución genética.
Objetivos: Esta investigación consistió en el análisis citogenético y molecular del cariotipo de una población transexual. Posteriormente se realizó el análisis molecular de siete polimorfismos genéticos, cuatro de repetición: ERα-rs3138774, ERβ-rs113770630, AR rs193922933 y CYP19-rs60271534, y tres polimorfismos de única base (SNPs): ERα-rs2234693, ERα-rs9340799 y CYP17-rs743572, en una población de 974 transexuales y 1.327 controles. El diagnóstico y selección de la muestra se realizó en las Unidades de Identidad de Género de los Hospitales Clínic (Barcelona) y Carlos Haya (Málaga).
Material y Métodos: El análisis del cariotipo se realizó mediante bandas G y el microarray Affymetrix CytoScan™ high-density. El estudio de los polimorfismos consistió en la amplificación de las regiones polimórficas y posterior establecimiento de los genotipos
mediante electroforesis capilar (3130 XL Genetic Analyzer), o mediante digestión enzimática en el caso de los polimorfismos de única base. El análisis de las frecuencias se realizó con los tests Mann-Whitney o Chi-cuadrado y el software SPSS® 23.0. El análisis
de interacción se realizó mediante regresión logística binaria con el software SNPStats.
Los falsos positivos se excluyeron con la corrección de Bonferroni.
Resultados: Los receptores de estrógenos alfa y beta están implicados en la base genética de la transexualidad. La población FtM mostró mayor número de repeticiones CA (ERβ-rs113770630) que la población control. Las frecuencias alélicas y genotípicas del ERα-
rs9340799 (genotipo A/A) fueron también significativas en la población FtM. Se encontraron combinaciones alélicas significativas entre ERα-rs9340799, ERβ-rs113770630 y AR-rs193922933 en la población MtF.
Conclusión: Los receptores de estrógenos alfa y beta juegan un papel clave en la diferenciación sexual del cerebro en nuestra especie.
... Generalno gledano sveukupni moždani volumen je veći kod muškaraca u odnosu na žene. Pre hormonskog tretmana slični volumeni natalnog pola su pronađeni kod odraslih [32,33,34] i adolescenata [35] sa rodnom disforijom. Muško-ženske transseksualne osobe (MuŽ TS) imaju totalni intrakranijalni volumen između onog kod muških (M) i ženskih (Ž) kontrolnih cisrodnih grupa (polno-rodno skladne) [32] . ...
... Frakciona anizotropija (FA) je tehnika merenja mikrostrukture bele mase koja je u širokoj upotrebi u neurobiološkim istraživanjima mozga. Mereno Difuzionim Tenzor Imidžingom (DTI) muškarci su imali veće vrednosti funkcionalne anizotropije od žena (odnosi se na rodno usaglašene-cisrodne osobe) [40,33] . Androfilne MuŽ osobe sa osećanjem rodne disforije koja je počela u detinjstvu su pre započinjanja hormonske terapije unakrsnim hormonima imali obrazac mikrostrukture bele mase koja se statistički razlikovala od M i Ž kontrole [33] . ...
... Mereno Difuzionim Tenzor Imidžingom (DTI) muškarci su imali veće vrednosti funkcionalne anizotropije od žena (odnosi se na rodno usaglašene-cisrodne osobe) [40,33] . Androfilne MuŽ osobe sa osećanjem rodne disforije koja je počela u detinjstvu su pre započinjanja hormonske terapije unakrsnim hormonima imali obrazac mikrostrukture bele mase koja se statistički razlikovala od M i Ž kontrole [33] . Njihove vrednosti su bile između M i Ž kontrola u pojedinim moždanim fascikulima desne hemisfere, izuzev u jednoj u kojoj su pokazali maskulini obrazac. ...
... While the understanding of binary cisgender regarding cognitive and personality traits has been established, we could further our clinical knowledge by researching transgender performance on such tasks. Studies on brain activity have also revealed that one's brain activity is more concurrent with his or her identifying gender (rather than assigned sex) (Rametti et al., 2011a;Rametti et al., 2011b). Therefore, it appears important to assess possible parallels between the performance of cisgender men with transmen, and cisgender women with transwomen. ...
... Additionally, across most cultures, men reportedly show more verbal and physical aggression, and have greater incidences of committing crimes (Archer, 2004); whereas women generally tend to express aggression through indirect or non-physical means, such as malicious gossip (Hess & Hagen, 2006). Current available research (although limited) appears to suggest the use of gender identity congruent norms use for interpretation (i.e., Lippa, 2010;Micah, 2000;Rametti et al., 2011a;Rametti et al., 2011b). There appears to be some evidence to support that applying gender identity congruent MMPI/-2 norms (in place of assigned sex norms) resulted in transgender profiles to be reported within normal limits on a majority, if not all, scales (Micah, 2000). ...
... In line with this framework, large-scale brain networks interactions between transmen (TM) and transwomen with gender incongruence, cismen (CM) and ciswomen (CW) have been described 4 . The reported functional connectivity differences between groups were explained by the complementarity of the two dominant hypotheses in understanding the brain differences between gender groups: i) a neurodevelopmental cortical hypothesis that suggests the existence of different brain phenotypes based on structural magnetic resonance imaging (MRI) data [5][6][7][8] and genes polymorphisms of sex hormone receptors 9 ; and ii) a functional-based hypothesis explained by differences in regions involved in the own body perception 10,11 . The most compelling nding was the reduced functional connectivity (FC) in regions of the salience network and its couplings with the default mode, the sensorimotor and the executive control networks when comparing the TM group with CM 4 . ...
... Among the available hypotheses to explain gender, some try to answer the question on why the gender is built in the brain and others on how the brain works in relation to gender. Within the framework of the why, we proposed a neurodevelopmental cortical hypothesis 8 by means of structural MRI techniques in transgender people before undergoing hormone a rming treatment [5][6][7] , that was later supported by brain functional MRI data 4 . Based on our previous ndings, TM have a mixture of masculine, feminine and defeminized morphological brain traits. ...
Large-scale brain network interactions have been described between trans- and cis -gender identities. However, a temporal perspective of the brain spontaneous fluctuations is missing. We investigated the functional connectivity dynamics in transmen with gender incongruence and its relationship with interoceptive awareness. We describe four states in native and meta-state spaces: i) one state highly prevalent with sparse overall connections; ii) a second with strong couplings mainly involving components of the salience, default and executive control networks. Two states with global sparse connectivity but positive couplings iii) within the sensorimotor network, and iv) between salience network regions. Transmen had more dynamical fluidity than cismen, while cismen presented less meta-state fluidity and range dynamism than transmen and ciswomen. A positive association between attention regulation and fluidity, and meta-state range dynamism was found in transmen. There exist gender differences in the temporal brain dynamism, characterized by distinct interrelations of the salience network as catalyst interacting with other networks. We provide a functional explanation to the neurodevelopmental hypothesis proposing different brain phenotypes in the construction of the gendered -self.
... None of the four studies included an explicit definition of "gender identity." The most elaborate were formulations such as "perceptions of the own sex" (Savic and Arver, 2011) or "the male controls have a gender identity as men (. . . ) and control women have a gender identity as women" (Rametti et al., 2011b). This is remarkably poor considering the centrality of gender identity in the research question. ...
... The Supplementary Materials include an extended report on the selection procedure and a full list of the analyzed terms. 6 I excludedRametti et al. (2011b) from the quantitative assessment because of the parallels in use of the terms toRametti et al. (2011a). ...
This study undertakes an analysis of the conceptualization of gender identity in neuroscientific studies of (trans)gender identity that contrast the brains of cisgender and transgender participants. The analysis focuses on instances of epistemic injustice that combine scientific deficiencies and the exclusion of relevant bodies of knowledge. The results of a content analysis show how the ignoring of biosocial, developmental, mosaicist, contextualist, and depathologizing approaches leads to internal conceptual inconsistencies, hermeneutical deficiencies and the upholding of questionable paradigms in the research field. Interviews with researchers involved in these brain studies reveal targeted and diffuse forms of testimonial injustice against alternative approaches, promoted by the hierarchical arrangements of research teams in combination with the careerist and economic logic of research. The analysis points to the exclusion of critical epistemologies of science and the historical oppression of trans people as epistemic agents as the underlying hermeneutical deficiencies.
... The rest of the studies, based on set of cases, are focused on neuroimaging and genetics. The GIU from Catalonia in collaboration with the UNED has described findings based on functional neuroimaging 149 , white matter microstructure [150][151][152] , cortical thickness 153,154 , and brain network interactions 155 in individuals with gender incongruence. The effects of cross-sex hormone treatment on white matter microestructure and on cortical thickness in transsexual individuals have also been evaluated 152,154 . ...
... It is noteworthy that an article on sociodemographic and clinical aspects exclusively of the Spanish population has been referenced 102 times in journals indexed in the SCI 177 , and another on the influence of hormonal treatment in reducing anxiety and depression in transsexual people, has received 95 citations 70 . Several neuroimaging studies have obtained an average of 52 citations per article [150][151][152] , or have been published in highly relevant journals according to the JCR quartile to which it belongs 124,153 . Although the benchmark with other countries are not established as research is constantly increasing and we lack similar comparison reviews, considering that the 75 most popular online articles in journals indexed in PubMed on transgender health have received an average of 63 citations 194 , we could state that a certain leadership has been achieved within international research. ...
Objective. To provide a bibliometric and contents analyses of the Spanish research in the field of gender dysphoria based on a literature review.
Method. Five international and four national databases, and two platforms were used to retrieve publications using
the keyword “gender dysphoria” and related terms. The results were combined with Spain and with the name of the Spanish cities’ names with a hospital. The articles published from the Gender Identity Units (GIU) being part of the National Health System were selected. The number of citations was assessed using the Science Citation Index (SCI) and Google Scholar.
Results. A total of 179 articles were included. Production shows a progressive increase from 1999 to 2015 and a slight decrease in the following years. 34.6% were published in English, 45.8% were based on set of cases, and the most frequent topic is psychology and mental health (58.1%). The 75 publications indexed in the SCI had received 1,252 citations, and the 152 found in Google Scholar reached 3,105 citations. The highest SCI average citation per article corresponds to those published in English (22.2), based on set of cases (21.1), in the field of neuroimaging (52), and coming from the Catalonia GIU (25.7).
Conclusions. The Spanish research on gender dysphoria produced from the GIUs has had a progressive growth, covers many topics, includes a high number of studies based on set of cases, and the number of citations reflect an impact on the scientific community and international leadership in some areas such as neuroimaging.
Key Words. Bibliometric analysis; Gender dysphoria; Gender Identity; Gen-
der incongruence; Gender unit; Spain; Review; Transsexualism; Transgender.
... More recent studies performed in our group with brain MRI and genetic polymorphisms on hormone receptors were in line of this hypothesis and refined it. Using structural MRI techniques, and controlling for the pre-pubertal onset of gender incongruence and sexual attraction of hormonally-naïve transgender people, we studied white matter microstructure (Rametti et al., 2011a(Rametti et al., , 2011b and cortical thickness (Zubiaurre-Elorza et al., 2014 differences of TM and TW in comparison with cisgender groups. Whereas TM had a morphological brain mix of masculine, feminine, and defeminized traits, TW showed a combination of feminine, masculine, and demasculinized traits. ...
... This may indeed provide support for the hypothesis of the Karolinska group on gender incongruence . Further supporting this structural underpinnings, we had also reported demasculinization of white matter microstructure in right and left superior longitudinal fasciculi, the anterior region of the cingulum, and fornix minor in TW, while these fasciculi are masculinized in TM (Rametti et al., 2011a(Rametti et al., , 2011b. ...
Functional brain organization in transgender persons remains unclear. Our aims were to investigate global and regional connectivity differences within functional networks in transwomen and transmen with early-in-life onset gender incongruence; and to test the consistency of two available hypotheses that attempted to explain gender variants: (i) a neurodevelopmental cortical hypothesis that suggests the existence of different brain phenotypes based on structural MRI data and genes polymorphisms of sex hormone receptors; (ii) a functional-based hypothesis in relation to regions involved in the own body perception. T2*-weighted images in a 3-T MRI were obtained from 29 transmen and 17 transwomen as well as 22 cisgender women and 19 cisgender men. Resting-state independent component analysis, seed-to-seed functional network and graph theory analyses were performed. Transmen, transwomen, and cisgender women had decreased connectivity compared with cisgender men in superior parietal regions, as part of the salience (SN) and the executive control (ECN) networks. Transmen also had weaker connectivity compared with cisgender men between intra-SN regions and weaker inter-network connectivity between regions of the SN, the default mode network (DMN), the ECN and the sensorimotor network. Transwomen had lower small-worldness, modularity and clustering coefficient than cisgender men. There were no differences among transmen, transwomen, and ciswomen. Together these results underline the importance of the SN interacting with DMN, ECN, and sensorimotor networks in transmen, involving regions of the entire brain with a frontal predominance. Reduced global connectivity graph-theoretical measures were a characteristic of transwomen. It is proposed that the interaction between networks is a keystone in building a gendered self. Finally, our findings suggest that both proposed hypotheses are complementary in explaining brain differences between gender variants.
... Overall, the results from studies investigating structural neuroanatomy are highly discrepant, mostly centered on a single or a small number of brain regions and in many cases even contradictory. Findings typically range from no differences between men and Tw (Savic and Arver 2011), differences between Tw and both men and women (Luders et al. 2009), to an intermediate position for Tw between male and female brains (Rametti et al. 2011). Whereas the first two studies examined gray matter volumetric differences, Rametti et al. (2011) investigated fractional anisotropy of white matter fibers. ...
... Findings typically range from no differences between men and Tw (Savic and Arver 2011), differences between Tw and both men and women (Luders et al. 2009), to an intermediate position for Tw between male and female brains (Rametti et al. 2011). Whereas the first two studies examined gray matter volumetric differences, Rametti et al. (2011) investigated fractional anisotropy of white matter fibers. Overall, these investigations indicate that specifically the hypothalamus and other subcortical structures seem to differ in either size or thickness between transgender and cisgender individuals. ...
The exact neurobiological underpinnings of gender identity (i.e., the subjective perception of oneself belonging to a certain gender) still remain unknown. Combining both resting-state functional connectivity and behavioral data, we examined gender identity in cisgender and transgender persons using a data-driven machine learning strategy. Intrinsic functional
connectivity and questionnaire data were obtained from cisgender (men/women) and transgender (trans men/trans women) individuals. Machine learning algorithms reliably detected gender identity with high prediction accuracy in each of the four groups based on connectivity signatures alone. The four normative gender groups were classified with accuracies ranging from 48% to 62% (exceeding chance level at 25%). These connectivity-based classification accuracies exceeded those obtained from a widely established behavioral instrument for gender identity. Using canonical correlation analyses,
functional brain measurements and questionnaire data were then integrated to delineate nine canonical vectors (i.e., brain-gender axes), providing a multilevel window into the conventional sex dichotomy. Our dimensional gender perspective captures four distinguishable brain phenotypes for gender identity, advocating a biologically grounded
reconceptualization of gender dimorphism.We hope to pave the way towards objective, data-driven diagnostic markers for gender identity and transgender, taking into account neurobiological and behavioral differences in an integrative modeling
approach.
... A possible sexual orientation bias should also be considered for findings of "in-between" FA values among TrM and TrW. Rametti and colleagues found such a pattern when comparing homosexual GD populations with heterosexual male and female controls Rametti, Carrillo, Gomez-Gil, Junque, Zubiarre-Elorza 2011). Kranz and colleagues,when investigating 23 TrM (19 homosexual), found no FA differences compared with control groups of mixed, albeit predominantly heterosexual, orientation, but did find significantly lower mean diffusivity compared with the female controls, indicating a "male-like" pattern (Kranz et al. 2014). ...
... As opposed to Cth, FA values are believed to reflect axonal packing and caliber and, perhaps, also the degree of myelinization (Lebel et al. 2008). With regard to sex hormones, FA is primarily influenced by testosterone and is typically higher in men (Huster et al. 2009;Menzler et al. 2011;Rametti, Carrillo, Gomez-Gil, Junque, Zubiarre-Elorza 2011;Inano et al. 2013;Kanaan et al. 2014). ...
Although frequently discussed in terms of sex dimorphism, the neurobiology of sexual orientation and identity is unknown. We report multimodal magnetic resonance imaging data, including cortical thickness (Cth), subcortical volumes, and resting state functional magnetic resonance imaging, from 27 transgender women (TrW), 40 transgender men (TrM), and 80 heterosexual (40 men) and 60 homosexual cisgender controls (30 men). These data show that whereas homosexuality is linked to cerebral sex dimorphism, gender dysphoria primarily involves cerebral networks mediating self-body perception. Among the homosexual cisgender controls, weaker sex dimorphism was found in white matter connections and a partly reversed sex dimorphism in Cth. Similar patterns were detected in transgender persons compared with heterosexual cisgender controls, but the significant clusters disappeared when adding homosexual controls, and correcting for sexual orientation. Instead, both TrW and TrM displayed singular features, showing greater Cth as well as weaker structural and functional connections in the anterior cingulate-precuneus and right occipito-parietal cortex, regions known to process own body perception in the context of self.
... Neuroimaging studies that aim to understand the neurobiology of gender identity indicate that some sexually dimorphic brain structures are more closely aligned with gender identity than with physical sex characteristics in transgender adults prior to treatment with gender-affirming hormones [19][20][21]. A similar trend was reported in studies of gray matter in youth with gender dysphoria [22]. ...
While individuals have demonstrated gender diversity throughout history, the use of medication and/or surgery to bring a person's physical sex characteristics into alignment with their gender identity is relatively recent, with origins in the first half of the 20th century. Adolescent gender-affirming care, however, did not emerge until the late 20th century and has been built upon pioneering work from the Netherlands, first published in 1998. Since that time, evolving protocols for gender-diverse adolescents have been incorporated into clinical practice guidelines and standards of care published by the Endocrine Society and World Professional Association for Transgender Health, respectively, and have been endorsed by major medical and mental health professional societies around the world. In addition, in recent decades, evidence has continued to emerge supporting the concept that gender identity is not simply a psychosocial construct but likely reflects a complex interplay of biological, environmental, and cultural factors. Notably, however, while there has been increased acceptance of gender diversity in some parts of the world, transgender adolescents and those who provide them with gender-affirming medical care, particularly in the USA, have been caught in the crosshairs of a culture war, with the risk of preventing access to care that published studies have indicated may be lifesaving. Despite such challenges and barriers to care, currently available evidence supports the benefits of an interdisciplinary model of gender-affirming medical care for transgender/gender-diverse adolescents. Further long-term safety and efficacy studies are needed to optimize such care.
... Some studies found regional brain patterns consistent with some alteration in brain sex differentiation. These include findings of regional brain masculinization among gynephilic transgender men (Simon et al., 2013;Zubiaurre-Elorza et al., 2013), feminization in androphilic transgender women (Luders et al., 2012;Simon et al., 2013;Zubiaurre-Elorza et al., 2013), or patterns in which gynephilic transgender men and androphilic transgender women were intermediate relative to cisgender men and women (Rametti et al., 2011a(Rametti et al., , 2011b. Other structural MRI studies found little-to-no differences between transgender and cisgender participants of the same sex assigned at birth (Hoekzema et al., 2015;Khorashad et al., 2020a). ...
Sexual orientation is a core aspect of human experience and understanding its development is fundamental to psychology as a scientific discipline. Biological perspectives have played an important role in helping to uncover the processes that contribute to sexual orientation development. Research in this field has relied on a variety of populations, including community, clinical, and cross-cultural samples, and has commonly focused on female gynephilia (i.e., female sexual attraction to adult females) and male androphilia (i.e., male sexual attraction to adult males). Genetic, hormonal, and immunological processes all appear to influence sexual orientation. Consistent with biological perspectives, there are sexual orientation differences in brain development and evidence indicates that similar biological influences apply across cultures. An outstanding question in the field is whether the hypothesized biological influences are all part of the same process or represent different developmental pathways leading to same-sex sexual orientation. Some studies indicate that same-sex sexually oriented people can be divided into subgroups who likely experienced different biological influences. Consideration of gender expression in addition to sexual orientation might help delineate such subgroups. Thus, future research on the possible existence of such subgroups could prove to be valuable for uncovering the biological development of sexual orientation. Recommendations for such future research are discussed.KeywordsSexual orientationDevelopmentGeneticsSex hormonesMaternal immune hypothesisGender expression
... 6 Some studies found regional brain patterns consistent with some alteration in brain sex differentiation. These include findings of regional brain masculinization among gynephilic transgender men (e.g., Simon et al., 2013;Zubiaurre-Elorza et al., 2013), feminization in androphilic transgender women (e.g., Simon et al., 2013;Zubiaurre-Elorza et al., 2013), or patterns in which gynephilic transgender men and androphilic transgender women were intermediate relative to cisgender men and women (e.g., Rametti et al., 2011aRametti et al., , 2011b. Other structural MRI studies found little-to-no differences between transgender and cisgender participants of the same sex assigned at birth (e.g., Hoekzema et al., 2015;Khorashad, Khazai, et al., 2020). ...
Sexual orientation is a core aspect of human experience and understanding its development is fundamental to psychology as a scientific discipline. Biological perspectives have played an important role in uncovering the processes that contribute to sexual orientation development. Research in this field has relied on a variety of populations, including community, clinical, and cross-cultural samples, and has commonly focused on female gynephilia (i.e., female sexual attraction to adult females) and male androphilia (i.e., male sexual attraction to adult males). Genetic, hormonal, and immunological processes all appear to influence sexual orientation. Consistent with biological perspectives, there are sexual orientation differences in brain development and evidence indicates that similar biological influences apply across cultures. An outstanding question in the field is whether the hypothesized biological influences are all part of the same process or represent different developmental pathways leading to same-sex sexual orientation. Some studies indicate that same-sex sexually oriented people can be divided into subgroups who likely experienced different biological influences. Consideration of gender expression in addition to sexual orientation might help delineate such subgroups. Thus, future research on the possible existence of such subgroups could prove to be valuable for uncovering the biological development of sexual orientation. Recommendations for such future research are discussed.
... Among the available hypotheses to explain gender, some try to answer the question of why gender is built in the brain and others on how the brain works in relation to gender. Within the framework of the why, we proposed a neurodevelopmental cortical hypothesis 8 by means of structural MRI techniques in transgender people before undergoing hormone affirming treatment [5][6][7] , that was later supported by brain functional MRI data 4 . Based on our previous findings, TM have a mixture of masculine, feminine and defeminized morphological brain traits. ...
Large-scale brain network interactions have been described between trans- and cis -gender binary identities. However, a temporal perspective of the brain's spontaneous fluctuations is missing. We investigated the functional connectivity dynamics in transmen with gender incongruence and its relationship with interoceptive awareness. We describe four states in native and meta-state spaces: (i) one state highly prevalent with sparse overall connections; (ii) a second with strong couplings mainly involving components of the salience, default, and executive control networks. Two states with global sparse connectivity but positive couplings (iii) within the sensorimotor network, and (iv) between salience network regions. Transmen had more dynamical fluidity than cismen, while cismen presented less meta-state fluidity and range dynamism than transmen and ciswomen. A positive association between attention regulation and fluidity and meta-state range dynamism was found in transmen. There exist gender differences in the temporal brain dynamism, characterized by distinct interrelations of the salience network as catalyst interacting with other networks. We offer a functional explanation from the neurodevelopmental cortical hypothesis of a gendered -self.
... Brain bundles connecting cortical regions and related to cognitive and emotional function show demasculinization in trans women and opposite in transmen. [21,22] There is a complex interaction of hormones, genes, and cephalic structure in the formation of gender identity. Sexually dimorphic gene expression has been identified in mammalian brain. ...
A mismatch between the birth sex of a person and psychological recognition of self (gender) leads to a gender
expression, which is at variance with the societal norms, and thus gives rise to a persistent distress, which is
known as gender incongruence (GI) (previously gender dysphoria). These persons are known as trans genders.
A subset of these individuals feels that they are trapped in the wrong sexed body and need to bring their physical
sex into alignment with their gender. The “gender” is already imprinted into the brain at birth, and hence cannot
be changed, but the physical sex of a person can be, through gender affirmation surgeries (GAS). There has been
relative paucity of data from India regarding medical and surgical affirmative management of trans-persons, and
hence, the authors present their experience in GAS together with current demography, hypothesis regarding
etiology and management, as carried out in India. Authors have been providing comprehensive affirmative
management to trans persons, through their multi-specialty gender identity clinic (GIC) sited in a tertiary
care hospital. Over past 27 years, the senior author has performed over 3,000 GAS. The authors have noticed
a 20- fold rise in presentation of these cases (from six cases per year in 1993 to now around 150 cases in
the year 2019), an observation, which is similar to the experience of large volume GICs worldwide, as well
as many recent publications. There has been a steep rise in the number of persons with GI worldwide,
and those reporting at GICs. In the face of this rising number, authors present their experience, together
with current demographics and management. Authors have also contributed to the first version of Indian
Standards of Care for persons with GI and people with differences in sexual development/orientation Indian
standards of care 1in November 2020.
... For many decades, the prevailing etiological hypothesis has been that GI results from an alteration in the "normative" or sextypical psychosexual development (Zucker et al. 2016) and that in transgender persons, the sex differentiation of the brain is opposed to the genitals (Swaab and Garcia-Falgueras 2009). This theory, however, has not been substantiated in brain imaging and behavioral studies of trans women (TrW), (persons who are assigned as males at birth, but identify as women) (Rametti, Carrillo, Gómez-Gil, Junque, Segovia, et al. 2011a;Luders et al. 2012;Zubiaurre-Elorza et al. 2014) or trans men (TrM), (persons who are assigned as females at birth, but identify as men) (Rametti, Carrillo, Gómez-Gil, Junque, Zubiarre-Elorza, et al. 2011b;Simon et al. 2013;Zubiaurre-Elorza et al. 2013;Manzouri et al. 2017;Burke et al. 2018). This also applies for studies combining TrW and TrM (Savic et al. 2010;Kranz et al. 2014;Hahn et al. 2015;Guillamon et al. 2016;Kreukels and Guillamon 2016;Burke et al. 2017;Feusner et al. 2017;Majid et al. 2020;Manzouri and Savic 2019). ...
Gender incongruence (GI) is characterized by a feeling of estrangement from the own body in the context of self. GI is often described in people who identify as transgender. The underlying mechanisms are unknown. Data from MRI measurements and tests of own body perception triggered us to pose a model that GI in transgender persons (TGI) could be associated with a disconnection within the brain circuits mediating the perception of own body as self. This is a departure from a previous model of sex atypical cerebral dimorphism, introducing a concept that better accords with a core feature of TGI. The present MRI study of 54 hormone naive transmen (TrM), 38 transwomen (TrW), 44 cismen and 41 ciswomen show that cortical gyrification, a metric that reflects early maturation of cerebral cortex, is significantly lower in transgender compared with cisgender participants. This reduction is limited to the occipito-parietal cortex and the sensory motor cortex, regions encoding own body image and body ownership. Moreover, the cortical gyrification correlated inversely with own body-self incongruence in these regions. These novel data suggest that GI in TGI may originate in the neurodevelopment of body image encoding regions. The results add potentially to understanding neurobiological contributors to gender identity.
... Further, we observed greater cingulum GFA in men than women. Prior research has also demonstrated greater whole brain white matter anisotropy in men than women (Inano et al., 2011;Manzouri and Savic, 2018;Menzler et al., 2011;Rametti et al., 2011;van Hemmen et al., 2017). However, no prior study has attempted to link sex differences in white matter microstructure to psychosocial stress reactivity. ...
The prefrontal cortex and limbic system are important components of the neural circuit that underlies stress and anxiety. These brain regions are connected by white matter tracts that support neural communication including the cingulum, uncinate fasciculus, and the fornix/stria-terminalis. Determining the relationship between stress reactivity and these white matter tracts may provide new insight into factors that underlie stress susceptibility and resilience. Therefore, the present study investigated sex differences in the relationship between stress reactivity and generalized fractional anisotropy (GFA) of the white matter tracts that link the prefrontal cortex and limbic system. Diffusion weighted images were collected and deterministic tractography was completed in 104 young adults (55 men, 49 women; mean age = 18.87 SEM = 0.08). Participants also completed self-report questionnaires (e.g., Trait Anxiety) and donated saliva (later assayed for cortisol) before, during, and after the Trier Social Stress Test. Results revealed that stress reactivity (area under the curve increase in cortisol) and GFA of the cingulum bundle varied by sex. Specifically, men demonstrated greater cortisol reactivity and greater GFA within the cingulum than women. Further, an interaction between sex, stress reactivity, and cingulum GFA was observed in which men demonstrated a positive relationship while women demonstrated a negative relationship between GFA and cortisol reactivity. Finally, trait anxiety was positively associated with the GFA of the fornix/stria terminalis - the white matter pathways that connect the hippocampus/amygdala to the hypothalamus. These findings advance our understanding of factors that underlie individual differences in stress reactivity.
... A brief outline of research into this broad topic provides some evidence for cause and or consequence of gender incongruence, including genes, epigenetics (Fernandez et al., 2020(Fernandez et al., , 2018Arnold, 2017;McCarthy & Arnold, 2011;Ngun et al., 2011;Jones & Lopez, 2014), hormones, Menger et al., 2010;McCarthy, De Vries, & Forger, 2017), neuroanatomy and function (Beking et al., 2020;Mueller et al., 2017;Kreukels & Guillamon, 2016;Burke, Manzouri, & Savic, 2017;Luders et al., 2009;Rametti et al., 2011;Savic & Arver, 2011;Smith et al., 2015), and environment (Tozzi et al., 2019;Gräff et al., 2011). As yet, none are conclusive. ...
The origins of bodily sex are well understood but consensus on origins for gender are missing. While gonadal sex and sexual orientation are accepted as emanating from genetic and hormonal templates, gender’s existence, when it is acknowledged, currently has so far emanated from either social origins or a nebulous ‘somewhere’ in the brain. Although the characteristics of sex-related behavior relative to the physicality of reproduction are clearly dimorphic, other cognitive behaviors relative to reproduction have not been explicitly identified and presented. This article synthesizes important research to present a biological location of gender as opposed to sex. These cognitive behaviors can be differentially linked with reproduction throughout the lifespan. A physiological location for gender in the human phenotype may help advance this research further.
... There have now been several dozen studies comparing brain measures between cis-and transgender participants (reviewed in Guillamon et al., 2016;Kreukels and Guillamon, 2016;Manzouri et al., 2017;Smith et al., 2015) with a wide range of findings. However, the only replicated one is that total brain volume (Kranz et al., 2014;Rametti et al., 2011;Savic and Arver, 2011;Spizzirri et al., 2018) and its correlates such as total GM volume (Hoekzema et al., 2015;Manzouri et al., 2017, Spizzirri et al., 2018 are typical of sex assignment at birth. These findings reinforce the view that brain volume, GM, and WM are merely scaled to the rest of anticipated body morphology and unrelated to gender identity or behavior. ...
With the explosion of neuroimaging, it is clear that sex/gender is a key covariate influencing brain structure and function. Here we synthesize three decades of human brain MRI and postmortem data, emphasizing meta-analyses and other large studies, but the result is few reliable sex/gender findings and many unreplicated claims. Males' brains are larger than females' from birth, stabilizing around 11% in adults. This size difference accounts for other reproducible male/female brain differences: gray/white matter ratio (larger in F), inter- versus intrahemispheric connectivity ratio (greater in F), and regional cortical and subcortical volumes (greater in M). However, regional cortical and subcortical sex/gender differences are highly unreliable and explain only about 1% of volume variance. Connectome studies of sex/gender difference are conflicted and rarely control from brain size. Task-based fMRI has also failed to find reproducible brain activation differences between men and women in verbal, spatial, or emotion processing due to high rates of false discovery. In sum, male/female brain differences are non-binary and trivial relative to the total variance across human populations. Properly speaking, the human brain is not sexually-dimorphic.
... Morphologic and functional brain characteristics of transgender individuals have been investigated in vivo with magnetic resonance imaging (MRI), in order to substantiate this etiological hypothesis with a biologic background. Regarding brain morphology, several studies supported this hypothesis especially in transwomen, showing a pattern in line with gender identity with regards to cortical thickness, regional gray matter volumes and white matter microstructure [7][8][9][10][11]. On the other hand, findings seem to be more conflicting in transmen when evaluating morphologic brain characteristics. ...
To date, MRI studies focused on brain sexual dimorphism have not explored the presence of specific neural patterns in gender dysphoria (GD) using gender discrimination tasks. Considering the central role of body image in GD, the present study aims to evaluate brain activation patterns with 3T-scanner functional MRI (fMRI) during gender face discrimination task in a sample of 20 hormone-naïve transgender and 20 cisgender individuals. Additionally, participants were asked to complete psychometric measures. The between-group analysis of average blood oxygenation level dependent (BOLD) activations of female vs. male face contrast showed a significant positive cluster in the bilateral precuneus in transmen when compared to the ciswomen. In addition. the transwomen group compared to the cismen showed higher activations also in the precuneus, as well as in the posterior cingulate gyrus, the angular gyrus and the lateral occipital cortices. Moreover, the activation of precuneus, angular gyrus, lateral occipital cortices and posterior cingulate gyrus was significantly associated with higher levels of body uneasiness. These results show for the first time the existence of a possible specific GD-neural pattern. However, it remains unclear if the differences in brain phenotype of transgender people may be the result of a sex-atypical neural development or of a lifelong experience of gender non-conformity.
... Genetics researchers point science toward the possible genetic underpinnings of trans experience (e.g., Hare et al., 2009;Henningsson et al., 2005;Reiner & Gearhart, 2004). Neurologists and anatomists point science toward the possible brain anatomy differences and similarities that could provide an explanation for trans experience (e.g., Kruijver et al., 2000;Rametti et al., 2011aRametti et al., , 2011bZhou et al., 1995). Other biologists suggest maternal hormonal influences (e.g., Cohen-Kettenis et al., 1999;Green & Young, 2009). ...
The central question of this Element is this: What does it mean to be transgender - in general and in specific ways? What does the designation mean for any individual and for the groups in which the individual exists? Biologically, what occurs? Psychologically, what transpires? The Element starts with the basics. The authors question some traditional assumptions, lay out some bio-medical information, and define their terms. They then move to the question of central concern, seen first in terms of the individual and then in terms of the group or society. They conclude with some implications, urging some new approaches to research and suggest some applications in the classroom and beyond.
... Whereas a fair amount of magnetic resonance imaging (MRI) research comparing trans-and cisgender adults has focused on structural brain differences in terms of white matter microstructure [57][58][59], cortical thickness [60,61], and white and grey matter volume [62][63][64][65][66], only one study (of Cohort 1) thus far has described morphological brain characteristics in TGD youth [67]. TGD participants (54 trans boys, 37 trans girls), as a combined sample of different treatment conditions, on a whole-brain level, showed no signs of any sex-atypical grey matter volumes and were thus comparable with the cisgender groups of the same sex assigned at birth. ...
Our 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.
... Alternatively, in male to female transsexuals who have not begun hormone treatment, the white matter was significantly different from both cisgender males and cisgender females, suggesting a deficit in the masculinization of white matter tract development. 96 Collectively, these data show the organizational and activational impact of hormones on white matter and suggest that processes remain labile well into adulthood. ...
Adolescence is a highly dynamic period of development, which includes the final organizational phases of neural maturation within the prefrontal cortex (PFC). The organizational events of neural pruning and myelination occur in a sex‐specific manner, potentially giving rise to the disparities in mood disorders in adulthood. Due to the extended developmental time period of the PFC, environmental insults, including psychosocial stressors, may play a major role in steering the maturation of this region. In this review, the literature surrounding the sex specific alterations that occur in the PFC in rodent models following adolescent stress will be discussed. This will be complimented by a brief review on the state of human research in PFC sex differences in the development of white matter and cytoarchitecture across the lifespan. Taken together, the impact of developmental psychosocial stress on the circuitry of the PFC and resulting adult phenotypes will be summarized with a focus on the importance of considering sex differences in order to build a better understanding of developmental influences on adult disorders. This article is protected by copyright. All rights reserved. This review discusses the impact of developmental psychosocial stress on the circuitry of the prefrontal cortex and resulting adult phenotypes with a focus on the importance of considering sex differences in order to build a better understanding of developmental influences on adult disorders.
... The white matter microstructure of TW prior to initiation of GAHT has been characterized by diffusion tensor imaging to be between control females and control males. [222][223][224][225] Hahn and colleagues 226 also described different structural connectivity networks in 21 TW prior to initiating GAHT compared with control females and males. Seiger and colleagues 227 analyzed brain MRIs of 14 TW (mean age 26.9 ± 6.1 years) at baseline and after at least 4 months (169 days ± SD 38 days) of continuous oral or transdermal oestradiol and anti-androgens (cyproterone acetate ± GnRHa ± finasteride) and found decreases in the hippocampal region, increases in the ventricles and a correlation between progesterone levels and changes in grey matter structure. ...
Transgender (trans) women (TW) were assigned male at birth but have a female gender identity or gender expression. The literature on management and health outcomes of TW has grown recently with more publication of research. This has coincided with increasing awareness of gender diversity as communities around the world identify and address health disparities among trans people. In this narrative review, we aim to comprehensively summarize health considerations for TW and identify TW-related research areas that will provide answers to remaining unknowns surrounding TW’s health. We cover up-to-date information on: (1) feminizing gender-affirming hormone therapy (GAHT); (2) benefits associated with GAHT, particularly quality of life, mental health, breast development and bone health; (3) potential risks associated with GAHT, including cardiovascular disease and infertility; and (4) other health considerations like HIV/AIDS, breast cancer, other tumours, voice therapy, dermatology, the brain and cognition, and aging. Although equally deserving of mention, feminizing gender-affirming surgery, paediatric and adolescent populations, and gender nonbinary individuals are beyond the scope of this review. While much of the data we discuss come from Europe, the creation of a United States transgender cohort has already contributed important retrospective data that are also summarized here. Much remains to be determined regarding health considerations for TW. Patients and providers will benefit from larger and longer prospective studies involving TW, particularly regarding the effects of aging, race and ethnicity, type of hormonal treatment (e.g. different oestrogens, anti-androgens) and routes of administration (e.g. oral, parenteral, transdermal) on all the topics we address.
... Neurological, Biological, Hormonal, and Genetic Basis of TGE Individual Identities Typically, children are assigned a sex in utero or at birth, based on external genitalia alone (Hughes et al. 2006;Hungerford et al. 1959;Minto et al. 2003). However, doctors rarely examine the white matter microstructure of the brain (Rametti et al. 2011a(Rametti et al. , 2011b, internal sex organs (Hughes et al. 2006;Hungerford et al. 1959;Minto et al. 2003), hormone levels (Berenbaum & Beltz 2016;Hare et al. 2009), or genetics (Foreman et al. 2019;Hare et al. 2009;Hungerford et al. 1959) for a more comprehensive and consistent understanding of a child's gender. A child could be born with male external genitalia but could have (1) female white matter microstructure, (2) female internal organs (uterus), (3) high levels of female hormones, or (4) non-fully male genetic structure (XXY), none of which can be seen by examining the external genitalia at birth. ...
The role of the social worker in the achievement of human rights is to assist individuals in their struggle for dignity and their attainment of their full potential. Ethical social work ensures just laws and practices that allow all persons to live without discrimination. The purpose of this paper is to present the practice and policy implications of the last five years of court cases regarding transgender and gender expansive (TGE) children and school systems in the USA. This paper outlines the legal justifications for revisions to the current procedures and policies of interacting with TGE children, including use of restrooms consistent with gender identity (RCGI). These recommended guidelines are designed to prevent ongoing human rights violations and create pathways for TGE children to live their lives congruently with their gender identity. Basic human rights for the TGE individual include policy improvements involving restrooms, locker rooms, showers, overnight accommodation, affirmed name, and identification for the child welfare, mental health, educational, medical, juvenile justice, and law enforcement systems.
... This is in contrast to older methods of grouping according to shared sex assigned at birth. In addition, this parallels the research by Rametti et al. (2011aRametti et al. ( , 2011b, which found that the sexually dimorphic white/gray matter patterns are more similar to those who share the same gender identity as opposed to assigned sex at birth. Thus, future research should be clear about how gender and/or sex are differentiated and operationalized and for what purpose, especially when analyzing between-groups and within-group differences. ...
The current study extended previous work on the Health Behavior Inventory-20, a multidimensional measure of health risk and promotion behaviors, in several ways. First, participants were diverse in gender, including both cisgender and transgender persons. Second, dimensionality was reassessed using exploratory factor analysis, which revealed four factors: Proper Use of Health Care Resources, Diet, Anger and Stress, and Substance Use. Third, based on these results, we applied and optimized classical test theory to develop the 12-item Health Behavior Inventory-Short Form. Fourth, the dimensionality of the Health Behavior Inventory-Short Form was assessed using confirmatory factor analysis on a separate sample, finding that the items loaded on the four specific factors as expected, and that the common factors model fit better than bifactor, hierarchical, and unidimensional models. This finding supports the use of the four subscale scores but not the use of a total score. Fifth, measurement invariance was assessed across five gender identity groups: cisgender men and women, transgender men and women, and nonbinary individuals. Evidence emerged for full configural and metric invariance for all factors, and for partial scalar invariance. Sixth, concurrent evidence emerged for the validity of the four specific factors by examining relationships with the Duke Health Profile. The results are discussed in relationship to previous literature, future research directions, applications to practice, and limitations. Data (N = 1,233, 34.3% transgender) were from community and college participants who responded to an online survey.
... The right-hemispheric differences between cis-homosexual and transgender groups, together with the confirmed aberration of FA in the (right) IFOF, provide compelling indications for the hypothesized different own body perception, specifically in transgender individuals. In line with our results, several previous neuroimaging studies found differences between trans-and cisgender groups particularly located in the right hemisphere 16,17,22,27,29 , more specifically in the right insula, (pre-) cuneus, temporo-parietal junction, orbito-frontal, medial frontal, and anterior cingulate cortex. These regions, and the right hemisphere in general have been reported to be involved in cognitive processes of (body) perception in relation to self, body ownership, ego-centric representation, and bodily self-consciousness [51][52][53][54][55] . ...
... Cabe mencionar que en un estudio previo Emory, Williams, Cole, Amparo y Meyer (1991) no fueron encontradas diferencias en esta estructura. En otro estudio (Rametti, Carrillo, Gómez-Gil, Junque, Zubiarre-Elorza, Segovia & Guillamon, 2011), utilizando la técnica de imagen de difusión de tensor (detecta cambios sutiles en substancia blanca) descubren que el fascículo longitudinal superior izquierdo, la región anterior del cíngulo, el forceps medium y el tracto corticoespinal de los TH-M difieren de las mujeres y los hombres en substancia blanca u organización axonal. Finalmente, existen también marcadores biológicos indirectos que pueden aportar información adicional acerca del origen de la transexualidad y de la influencia que tiene la organización cerebral prenatal por factores hormonales, genéticos. ...
... Según la literatura científica reciente, en la experiencia de la transexualidad intervienen múltiples procesos (Bakker, 1993, Gooren, 2006 pero, crecientemente los factores biológicos han adquirido mayor peso. En particular, se enfatiza la importancia de los esteroides sexuales en cerebro y el neurodesarrollo, amparados por estudios de neuroimagen y genéticos (Zou et al., 1995, Kruijver et al., 2000, Luders et al., 2009, Flor et al., 2010, Rametti et al., 2011Savic et al., 2011, Bao et al., 2011, Pepper et al., 2011y Hernández 2013. Por ejemplo, Bao et al., (2011) encontraron que los cerebros de las mujeres trans con y sin tratamiento hormonal presentan características similares a los cerebros de las mujeres biológicas, mientras que los cerebros de los hombres trans son más cercanos a los de los hombres. ...
Diálogos y tensiones entre perspectivas de atención a la salud Diálogos y tensiones entre perspectivas de atención a la salud ¿Qué condiciones participan en la posibilidad de que las mujeres puedan prevenir el VIH o conocer su diagnóstico oportunamente y recibir la atención médica que requieren? Este volumen busca explorar estas cuestiones en un esfuerzo colectivo por comprender y difundir aspectos fundamentales de la condición de las mujeres en la epidemia. A través de infor-mación producida por la experiencia en el campo de la aten-ción a la salud, antropólogas, mujeres acompañantes pares y mujeres que viven con el virus, psicólogas sociales y sociólogos, funcionarias/os encargadas de políticas públicas, y médicas y médicos buscan en este libro tender puentes entre prácticas y saberes diversos. En él se invita al lector a que entable entre estos enfoques y problemas un diálogo que invite a ir más allá de una aproximación biomédica, en tanto se discuten procesos sociales, institucionales y subjetivos que marcan la experiencia de vivir con VIH para las mujeres en nuestro país.
... Algunas hipótesis sugieren que la disforia surge de la discrepancia entre el sexo cerebral y el gonadal . Las mujeres y los hombres transexuales muestran una morfología cerebral característica (Gómez-Gil et al., 2012;Guillamón et al., 2016;Rametti, Carrillo, Gómez-Gil, Junque, Zubiarre-Elorza, et al., 2011;Zubiaurre-Elorza et al., 2013) reflejo de un fenotipo cerebral contrario a su sexo genético (Smith et al., 2015) y consecuencia de un efecto atípico de las hormonas sexuales en regiones corticales específicas . Otros factores podrían también contribuir a la DG (Cohen-Kettenis y Gooren, 1999;Heylens et al., 2012;Savic, Garcia-Falgueras y Swaab, 2010), pero las evidencias actuales señalan la importancia de una vulnerabilidad genética. ...
Gender Dysphoria (GD) (American Psychiatric Association, 2013) is characterized by a
marked incongruence between gender and biological sex (World Health Organization,
1993). They have undergone a social transition from male-to-female (MtF) or femaleto-
male (FtM) that in many cases involves a somatic transition through cross-sex
hormone treatment and genital surgery.
The etiology of the GD is complex. Different hypothesis point out the presence of a sex
cerebral phenotype no consistent with the biological sex (Guillamón et al. 2016). In
addition, differences have been reported by studies of genetic polymorphisms in steroid
receptors and enzymes implicated in the sexual differentiation of brain, finding a direct
relation between both ER (α and β), AR and GD.
Due to the implication of the ERα in the GD, and since this receptor is involved in the
cerebral masculinization, the aim of the present work is to investigate the implication of
the polymorphism rs9478245, situated in the ERα gene (ESR1), in GD. The molecular
analysis of the polymorphism rs9478245 was carried out by the digestion with the
enzyme BsrDI in a sample of 74 FtMs, 74 MtFs, 74 men controls and 74 female
controls. Our results from the allele and genotype frequencies did not show significant
differences between FtM vs. Control XX, and MtF vs. Control XY. Our data confirm
that the polymorphism rs9478245 is not involved in the genetic basis of GD.
Keywords: ESR1; estrogen receptor; Female-to-male; Gender Dysphoria; Male-tofemale;
rs9478245 polymorphism.
... Moreover, this research group reported significant differences between MtF transgenders and both male and female controls in the superior longitudinal fasciculus, corticospinal tract, forceps minor and anterior cingulum. 39) They suggested that some fascicles do not complete the masculinization of the brain in MtF transgenders. In another study, Kranz et al. 40) investigated the white matter microstructure pattern of untreated transgender individuals with early-onset gender incongruence using DTI. ...
Transsexualism refers to a condition or belief which results in gender dysphoria in individuals and makes them insist that their biological gender is different from their psychological and experienced gender. Although the etiology of gender dysphoria (or transsexualism) is still unknown, different neuroimaging studies show that structural and functional changes of the brain result from this sexual incongruence. The question here is whether these reported changes form part of the etiology of transsexualism or themselves result from transsexualism culture, behaviors and lifestyle. Responding to this question can be more precise by consideration of cultural neuroscience concepts, particularly the culture–behavior–brain (CBB) loop model and the interactions between behavior, culture and brain. In this article, we first review the studies on the brain of transgender people and then we will discuss the validity of this claim based on the CBB loop model. In summary, transgender individuals experience change in lifestyle, context of beliefs and concepts and, as a result, their culture and behaviors. Given the close relationship and interaction between culture, behavior and brain, the individual’s brain adapts itself to the new condition (culture) and concepts and starts to alter its function and structure.
Differences between the two genders are widespread in nature (Fig. 17.1) and concern a variety of characteristics, including not only the external appearance but also inclinations and skills, as well as the way of thinking and the overall behavior.
Transgender veterans have a long history with the military. They face a variety of health and social disparities, which affect areas such as housing and employment. Transgender clients are also more likely to experience suicidal ideation, attempt suicide, and experience other mental health disorders. Furthermore, this population utilizes health care at a lower rate than others. Transgender veterans are more likely to experience military sexual trauma while previously on active duty with rates as high as one in five transmen are sexually assaulted. This chapter further explores the unique experiences of both male to female (MTF) and female to male (FTM) transgender veterans. Treatment considerations, including responding to and providing holistic treatment as well as psychological assessment and guidelines for hormone therapy, are further explored and discussed.KeywordsTransgenderVeteran MTFVeteran FTMGender non-conformingTGNCHormone therapy
Introduction: There is increasing public and research interest in transgender people and communities. Coupled with this interest is a renewed pursuit of research into the possible biological origins of transgender identity. In this review, we critically examine the biological literature which explores the etiology of transgender identity, including endocrinological, behavioral, genetic, and neuroimaging studies, with the goal of identifying key trends in this literature, limitations, critical gaps, and future directions. Methods: We searched the Pubmed database for peer reviewed original experimental research conducted since 1990, using a combination of six transgender identity-related search terms and 18 topic search terms. Results: A total of 102 articles across the disciplines of endocrinology, genetics, cognitive function, and neuroanatomy met our review criteria. Most studies were conducted at gender identity clinics. Several approaches yielded compelling results, but where replication has been attempted, results have varied. We identified several issues in experimental design and/or interpretation that might account for this inconsistency. Conclusion: A number of research studies have investigated biological factors that could potentially contribute to transgender identity, but results often contradict each other. Interpretation of etiological studies of transgender identity can be misunderstood and/or misused by media, politicians, and care providers, placing transgender people at risk. We question the utility of etiological studies in clinical care, given that transgender identity is not pathological. When etiological studies are undertaken, we recommend new, inclusive designs for a rigorous and compassionate approach to scientific practice in the service of transgender communities and the providers who serve them.
Background
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.
La noción de comprensión ha sido objeto de un renovado interés dentro de los estudios dedicados a la filosofía de la ciencia. Si bien la mayor parte de las caracterizaciones se han valido de los conceptos epistemológicos tradicionales de verdad y conocimiento, la reciente literatura concerniente a la modelización científica ha puesto en cuestión la validez y el alcance de las mismas. Este es el motivo por el cual han surgido diversas propuestas que han planteado la necesidad de desplazar el foco de análisis de la verdad al uso pragmático. El objetivo de la comunicación consistirá en argumentar a favor de esta última tendencia. Para ello, se evaluarán las virtudes y defectos de una de las principales propuestas pragmáticas de la actualidad, la teoría de Henk de Regt. A fin de superar sus dificultades y mostrar la viabilidad de la propuesta pragmática, se articulará una noción alternativa de comprensión.
Book is on Sustainable Development Goals 17 Each goal has been describe chapter wise from Goal 1-17
El término identidad de género se refiere “al concepto más íntimo de una persona de sí mismo como hombre, mujer, una mezcla de ambos o ninguno” (Gómez-Gil, 2019; Human Rights Campaign, n.d.), mientras que el sexo hace referencia fundamentalmente, a las características biológicas. Aunque suele existir una concordancia entre género y sexo (población cis), puede ocurrir que la identidad de género difiera del sexo asignado en el momento del nacimiento (población trans). Así, la incongruencia de género (IG) en el ICD-11 (World Health Organization, 2018) se caracteriza por una marcada incongruencia entre el género sentido y el sexo asignado al nacer.
En 2020, Gómez-Gil y colaboradores realizaron una amplia revisión de la literatura, identificando las principales aportaciones y el impacto internacional de la investigación española sobre la IG realizada desde las Unidades de Identidad de Género (UIG) españolas. Su objetivo fue clasificar por contenido toda la producción científica española de los últimos 20 años sobre la IG (197 publicaciones). El objetivo del presente trabajo consistió en el análisis socio demográfico y psicológico de la población con IG española atendida en las UIGs en el periodo 2000-2020, a partir del análisis de los artículos seleccionados por Gómez Gil et al., (2020).
This review systematically explored structural, functional, and metabolic features of the cisgender brain compared with the transgender brain before hormonal treatment and the heterosexual brain compared to the homosexual brain from the analysis of the neuroimaging literature up to 2018, and identified and discussed subsequent studies published up to March 2021. Our main aim was to help identifying neuroradiological brain features that have been related to human sexuality to contribute to the understanding of the biological elements involved in gender identity and sexual orientation. We analyzed 39 studies on gender identity and 24 on sexual orientation. Our results suggest that some neuroanatomical, neurophysiological, and neurometabolic features in transgender individuals resemble those of their experienced gender despite the majority resembling those from their natal sex. In homosexual individuals the majority resemble those of their same-sex heterosexual population rather than their opposite-sex heterosexual population. However, it is always difficult to interpret findings with noninvasive neuroimaging. Given the gross nature of these measures, it is possible that more differences too subtle to measure with available tools yet contributing to gender identity and sexual orientation could be found. Conflicting results contributed to the difficulty of identifying specific brain features which consistently differ between cisgender and transgender or between heterosexual and homosexual groups. The small number of studies, the small-to-moderate sample size of each study, and the heterogeneity of the investigations made it impossible to meta-analyze all the data extracted. Further studies are necessary to increase the understanding of the neurological substrates of human sexuality.
Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists
William Byne 1 2, Dan H Karasic 3, Eli Coleman 4, A Evan Eyler 5, Jeremy D Kidd 6, Heino F L Meyer-Bahlburg 7, Richard R Pleak 8, Jack Pula 9
PMID: 29756044 PMCID: PMC5944396 DOI: 10.1089/trgh.2017.0053
Free PMC article
Abstract
Regardless of their area of specialization, adult psychiatrists are likely to encounter gender-variant patients; however, medical school curricula and psychiatric residency training programs devote little attention to their care. This article aims to assist adult psychiatrists who are not gender specialists in the delivery of respectful, clinically competent, and culturally attuned care to gender-variant patients, including those who identify as transgender or transsexual or meet criteria for the diagnosis of Gender Dysphoria (GD) as defined by The Diagnostic and Statistical Manual of Mental Disorders (5th edition). The article will also be helpful for other mental health professionals. The following areas are addressed: evolution of diagnostic nosology, epidemiology, gender development, and mental health assessment, differential diagnosis, treatment, and referral for gender-affirming somatic treatments of adults with GD.
Keywords: assessment; gender dysphoria; gender transition; intersex; mental health; psychiatry; transgender.
Transgender persons identify with a gender
different from the one they were assigned at birth.
Although describing oneself as transgender is not a new
phenomenon, media attention has lately been increasing exponentially, thanks to progressive changes in
laws and change in societal attitudes. These changes
also allow more people nowadays to (openly) identify
as transgender and/or seek gender-affirming treatment. However, simultaneously, not much is presently
understood about the underlying neurobiology, and
specifically the brain structure and brain function of
transgender persons. One major question in neuroimaging and neuroscience has been to determine
whether, at the brain level, transgender people resemble more their gender identity, their sex assigned at
birth, or have a unique neural profile. Although the
evidence is presently inconsistent, it suggests that
while the brain structure, at least before hormonal
treatment, is more similar to sex assigned at birth, it
may shift with hormonal treatment. By contrast, on
“sex-stereotypical tasks,” brain function may already
be more similar to gender identity in transgender persons, also before receiving gender-affirming hormone
treatment. However, studies continue to be limited by
small sample sizes and new initiatives are needed to
further elucidate the neurobiology of a ‘brain gender’
(sex-dimorphic change according to one’s gender).
Keywords: cross-sex hormones; gender; magnetic resonance imaging; neurobiology; trans
The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions.
Several theories of the etiology of gender incongruity have been proposed to explain the origins of the condition. Historically, individuals who were uncomfortable in their birth-assigned sex were thought to suffer from severe psychopathology. As technology advanced and more individuals sought treatment, biological theories emerged and replaced psychoanalytic theories. It became evident that although people may experience distress with their birth-assigned sex, this was not, in and of itself, a pathological disorder. An assemblage of research emerged supporting a biological basis for the condition. Researchers have found evidence of several areas in the brain that differ in transgender and non-transgender individuals. Twin and familial studies suggest a genetic component, and some researchers have explored specific genes of the androgen and estrogen receptors. Early hormonal influences on the brain appear to account for different brain phenotypes and may ultimately provide answers to the origins of gender incongruence.
Over the past decade, more and more children and adolescents are identifying as transgender and gender diverse (TGD). Often, they and their parents first turn to their primary care pediatrician for guidance and support. Therefore, in 2018, the American Academy of Pediatrics (AAP) released a policy statement focusing on the health care of TGD youth.4 The AAP acknowledges that many pediatricians have a lack of training in this area and therefore need to increase their knowledge base and expertise in order to provide culturally competent care. While most sexual and gender minority individuals are healthy and well adjusted, some TGD youth are at an increased risk of mental health concerns, including anxiety, depression, substance abuse, eating disorders and suicidality. This is theorized to be due to the experienced or internalized marginalization, stigmatization, victimization, harassment or rejection and not inherent in having gender dysphoria or being transgender. The pediatrician therefore needs to be knowledgeable of, and skilled to screen for, the health disparities that may exist, as well as to be able to support the individual who may disclose their gender identity status during treatment. Parents and guardians may also turn to the pediatrician for guidance when faced with their child who presents with gender non-conforming behaviors or gender dysphoria. Therefore the pediatrician needs to be able to guide the parents as well, as their acceptance and support of their child's journey to gender identity is probably the most important protective factor against health disparities encountered. To deliver optimum care for TGD children and youth, the pediatrician needs to establish an office setting that is inclusive, gender-neutral and TGD friendly. By becoming familiar with the diversity of gender expression and identities, use of gender-appropriate terminology, health disparities often encountered and the importance of providing a safe and welcoming environment, issues that are all covered in this article, the primary care pediatrician will be in position to provide comprehensive health care to this often marginalized population.
Gender 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.
Transgender 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 estrogen 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 estrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs controls) ‐ regions showing greater pretreatment 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.
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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.
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.
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.
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.
In the human brain, different regions of the cortex communicate via white matter tracts. Investigation of this connectivity is essential for understanding brain function. It has been shown that trajectories of white matter fiber bundles can be estimated based on orientational information that is obtained from diffusion tensor imaging (DTI). By extrapolating this information, cortical regions associated with a specific white matter tract can be estimated. In this study, we created population-averaged cortical maps of brain connectivity for 4 major association fiber tracts, the corticospinal tract (CST), and commissural fibers. It is shown that these 4 association fibers interconnect all 4 lobes of the hemispheres. Cortical regions that were assigned based on association with the CST and the superior longitudinal fasciculus (SLF) agreed with locations of their known (CST: motor) or putative (SLF: language) functions. The proposed approach can potentially be used for quantitative assessment of the effect of white matter abnormalities on associated cortical regions.
Transsexuality is an individual's unshakable conviction of belonging to the opposite sex, resulting in a request for sex-reassignment surgery. We have shown previously that the bed nucleus of the stria terminalis (BSTc) is female in size and neuron number in male-to-female transsexual people. In the present study we investigated the hypothalamic uncinate nucleus, which is composed of two subnuclei, namely interstitial nucleus of the anterior hypothalamus (INAH) 3 and 4. Post-mortem brain material was used from 42 subjects: 14 control males, 11 control females, 11 male-to-female transsexual people, 1 female-to-male transsexual subject and 5 non-transsexual subjects who were castrated because of prostate cancer. To identify and delineate the nuclei and determine their volume and shape we used three different stainings throughout the nuclei in every 15th section, i.e. thionin, neuropeptide Y and synaptophysin, using an image analysis system. The most pronounced differences were found in the INAH3 subnucleus. Its volume in thionin sections was 1.9 times larger in control males than in females (P < 0.013) and contained 2.3 times as many cells (P < 0.002). We showed for the first time that INAH3 volume and number of neurons of male-to-female transsexual people is similar to that of control females. The female-to-male transsexual subject had an INAH3 volume and number of neurons within the male control range, even though the treatment with testosterone had been stopped three years before death. The castrated men had an INAH3 volume and neuron number that was intermediate between males (volume and number of neurons P > 0.117) and females (volume P > 0.245 and number of neurons P > 0.341). There was no difference in INAH3 between pre-and post-menopausal women, either in the volume (P > 0.84) or in the number of neurons (P < 0.439), indicating that the feminization of the INAH3 of male-to-female transsexuals was not due to estrogen treatment. We propose that the sex reversal of the INAH3 in transsexual people is at least partly a marker of an early atypical sexual differentiation of the brain and that the changes in INAH3 and the BSTc may belong to a complex network that may structurally and functionally be related to gender identity.
Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psychogenic 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 terminals (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.
Several years ago we hypothesized that the vomeronasal system (VNS), a complex neural network involved in the control of reproductive behavior, might be sexually dimorphic. This hypothesis sprung from several facts; (a) the existence of steroid receptors in the VNS; (b) sexual dimorphism was already described in some structures that receive vomeronasal input, such as the medial preoptic area, the ventromedial hypothalamic nucleus, the ventral region of the premammillary nucleus and the medial amygdaloid nucleus; and (c) the vomeronasal organ, which is the receptor organ of the VNS, was also sexually dimorphic. After that point, the accessory olfactory bulb (AOB), the bed nucleus of the accessory olfactory tract (BAOT) and the bed nucleus of the stria terminalis were found to be sexually dimorphic. The aim of the present review is to show the experimental facts that confirm our earlier hypothesis and, consequently, to present the existence of a sexually dimorphic multisynaptic pathway for the first time in mammals. Sexual dimorphism in the VNS might provide a comprehensive approach to understanding the neural bases of sexually dimorphic reproductive behavior and it is suggested here that the greater number of neurons which male rats present in relation to females in most VNS structures might contribute to the inhibition of the expression of feminine copulatory behavior (lordosis) and maternal behavior in males. In addition, the mechanisms that control the development of sexual dimorphism in the VNS are discussed. The discussion takes into account the two patterns of sexual dimorphism found in the rat brain. Estrogens seem to promote the development of sexual dimorphism in both male and female rats. However, an inhibitory role of androgens might be necessary to hypothesize when males or females present a lower number of neurons and/or volume than the opposite sex. There are experimental data supporting this hypothesis in the female, since dihydrotestosterone seems to facilitate neuronal death in VNS structures, such as the AOB and the BAOT, in which females present a lower number of neurons and volume than male rats. Finally, since the lateral division of the bed nucleus of the stria terminalis, which belongs to the main olfactory system (MOS), is sexually dimorphic and presents anatomical relationships with some VNS structures the MOS might be sexually dimorphic.
Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis (BSTc) was based on a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin-expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity, and past or present hormonal status. Regardless of sexual orientation, men had almost twice as many somatostatin neurons as women (P < 0.006). The number of neurons in the BSTc of male-to-female transsexuals was similar to that of the females (P = 0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.
Male 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.
The olfactory system (accessory) implicated in reproductive physiology and behavior in mammals is sexually dimorphic. These brain sex differences present two main characteristics: they are seen in neural circuits related to sexual behavior and sexual physiology and they take one of two opposite morphological patterns (male>female or female>male). The present work reports sex differences in the olfactory system in a large homogeneous sample of men (40) and women (51) using of voxel-based morphology. Gray matter concentration showed sexual dimorphism in several olfactory regions. Women have a higher concentration in the orbitofrontal cortex involving Brodmann's areas 10, 11 and 25 and temporomedial cortex (bilateral hippocampus and right amygdala), as well as their left basal insular cortex. In contrast, men show a higher gray matter concentration in the left entorhinal cortex (Brodmann's area 28), right ventral pallidum, dorsal left insular cortex and a region of the orbitofrontal cortex (Brodmann's area 25). This study supports the hypothesis that the mammalian olfactory system is a sexually dimorphic network and provides a theoretical framework for the morphofunctional approach to sex differences in the human brain.
Previous studies have found developmental differences between males and females in brain structure. During childhood and adolescence, relative white matter volume increases faster in boys than in girls. Sex differences in the development of white matter microstructure were investigated in a cohort of normal children ages 5-18 in a cross-sectional diffusion tensor imaging (DTI) study. Greater fractional anisotropy (FA) in boys was shown in associative white matter regions (including the frontal lobes), while greater FA in girls was shown in the splenium of the corpus callosum. Greater mean diffusivity (MD) in boys was shown in the corticospinal tract and in frontal white matter in the right hemisphere; greater MD in girls was shown in occipito-parietal regions and the most superior aspect of the corticospinal tract in the right hemisphere. Significant sex-age interactions on FA and MD were also shown. Girls displayed a greater rate of fiber density increase with age when compared with boys in associative regions (reflected in MD values). However, girls displayed a trend toward increased organization with age (reflected in FA values) only in the right hemisphere, while boys displayed this trend only in the left hemisphere. These results indicate differing developmental trajectories in white matter for boys and girls and the importance of taking sex into account in developmental DTI studies. The results also may have implications for the study of the relationship of brain architecture with intelligence.
One working hypothesis behind transsexuality is that the normal sex differentiation of certain hypothalamic networks is altered. We tested this hypothesis by investigating the pattern of cerebral activation in 12 nonhomosexual male-to-female transsexuals (MFTRs) when smelling 4,16-androstadien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST). These steroids are reported to activate the hypothalamic networks in a sex-differentiated way. Like in female controls the hypothalamus in MFTRs activated with AND, whereas smelling of EST engaged the amygdala and piriform cortex. Male controls, on the other hand, activated the hypothalamus with EST. However, when restricting the volume of interest to the hypothalamus activation was detected in MFTR also with EST, and explorative conjunctional analysis revealed that MFTR shared a hypothalamic cluster with women when smelling AND, and with men when smelling EST. Because the EST effect was limited, MFTR differed significantly only from male controls, and only for EST-AIR and EST-AND. These data suggest a pattern of activation away from the biological sex, occupying an intermediate position with predominantly female-like features. Because our MFTRs were nonhomosexual, the results are unlikely to be an effect of sexual practice. Instead, the data implicate that transsexuality may be associated with sex-atypical physiological responses in specific hypothalamic circuits, possibly as a consequence of a variant neuronal differentiation.
The aim of this study was to examine the characteristics of transsexuals from Spain. A total of 252 consecutive applicants for sex reassignment were evaluated using a standardized semistructured clinical interview and the Mini International Neuropsychiatric Interview (Spanish Version 5.0.0) to record demographic, clinical, and psychiatric data. Transsexualism was diagnosed in 230 patients, with a male to female (MF)/female to male (FM) ratio of 2.2:1. Transsexual patients frequently had low employment status, lived with their parents, and mainly had a sexual orientation toward same-sex partners. The most frequent psychiatric diagnoses were adjustment disorder and social phobia in both groups, and alcohol and substance-related disorders in the MF group. MF transsexuals were older than FM transsexuals when requesting sex reassignment, but did not differ in age when starting hormonal therapy (often on their own); fewer MFs were in employment requiring high educational qualification, more were non-Spanish natives, and more had previous and current histories of alcohol and substance abuse or dependence. The basic characteristics of transsexuals from Spain were similar to those of other European countries, except for the higher proportion of patients living with their parents and the higher proportion of MFs who reported same-sex sexual orientation compared with previous studies.
Each of the descending pathways involved in motor control has a number of anatomical, molecular, pharmacological, and neuroinformatic characteristics. They are differentially involved in motor control, a process that results from operations involving the entire motor network rather than from the brain commanding the spinal cord. A given pathway can have many functional roles. This review explores to what extent descending pathways are highly conserved across species and concludes that there are actually rather widespread species differences, for example, in the transmission of information from the corticospinal tract to upper limb motoneurons. The significance of direct, cortico-motoneuronal (CM) connections, which were discovered a little more than 50 years ago, is reassessed. I conclude that although these connections operate in parallel with other less direct linkages to motoneurons, CM influence is significant and may subserve some special functions including adaptive motor behaviors involving the distal extremities.
Adapting decision making according to dynamic and probabilistic changes in action-reward contingencies is critical for survival in a competitive and resource-limited world. Much research has focused on elucidating the neural systems and computations that underlie how the brain identifies whether the consequences of actions are relatively good or bad. In contrast, less empirical research has focused on the mechanisms by which reinforcements might be used to guide decision making. Here, I review recent studies in which an attempt to bridge this gap has been made by characterizing how humans use reward information to guide and optimize decision making. Regions that have been implicated in reinforcement processing, including the striatum, orbitofrontal cortex, and anterior cingulate, also seem to mediate how reinforcements are used to adjust subsequent decision making. This research provides insights into why the brain devotes resources to evaluating reinforcements and suggests a direction for future research, from studying the mechanisms of reinforcement processing to studying the mechanisms of reinforcement learning.
Diffusion tensor imaging (DTI) tractography allows perform virtual dissections of white matter pathways in the living human brain. In 2002, Catani et al. published a method to reconstruct white matter pathways using a region of interest (ROI) approach. The method produced virtual representations of white matter tracts faithful to classical post-mortem descriptions but it required detailed a priori anatomical knowledge. Here, using the same approach, we provide a template to guide the delineation of ROIs for the reconstruction of the association, projection and commissural pathways of the living human brain. The template can be used for single case studies and case-control comparisons. An atlas of the 3D reconstructions of the single tracts is also provided as anatomical reference in the Montreal Neurological Institute (MNI) space.
Bobes, J., Gutierrez, M., Palao, D., Ferrando, L., Gibert-Rahola, J.,Lecrubier, Y., et al. (1997). Validez del M.I.N.I. (Mini Interna-tional Neuropsychiatric Interview) en tres centros de AP enEspan ̃a [The validity of the M.I.N.I. (Mini International Neuro-psychiatric Interview) in three Spanish primary care centers].Psiquiatría Biológica, 4(Suppl. 2), 79
Introduction:
It has been hypothesized that cognitive and memory-related brain function in transsexuals during cross-sex hormonal treatment might be activated towards that of the subjective gender. However, research on this topic has produced inconsistent results, and to the best of our knowledge no studies have investigated memory changes in androgen-treated female-to-male (FM) transsexuals.
Methods:
A total of 33 FM transsexuals underwent neuropsychological testing in order to examine the effects of androgen on memory. We used a longitudinal design in which 14 FM transsexuals were tested twice, before and after receiving 6 months of testosterone treatment. In addition, a cross-sectional design was used to compare 10 individuals off treatment versus 9 individuals on testosterone treatment for at least 6 months.
Results:
Participants tested before and after 6 months of androgen treatment improved significantly their performance on a visual memory task (visual paired associates, immediate recall, WMS-R). The cross-sectional design confirmed that patients on androgen treatment for at least 6 months performed better than subjects off treatment on the same task and also on another visual memory task (Rey-Osterrieth complex figure test, ROCF; copy and delayed recall). No differences were found in any verbal memory test for either design.
Conclusions:
The results indicate that androgen has an influence on visual memory, but not on verbal memory. Therefore, for FM transsexuals the data support an activating effect for androgens on visual memory, a domain that generally tends to favour males.
Diffusion tensor imaging (DTI) is an increasingly used method for investigation of brain white matter integrity in both research and clinical applications. Familiarity with normal variation of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and measurement reproducibility is essential when DTI measurements are interpreted in clinical patients.
To establish normal values for FA and ADC in a healthy adult population at 1.5 T and 3 T MRI based on region of interest (ROI) analysis, and to study the inter- and intra-observer reproducibility of the measurements.
Forty healthy volunteers (26 women, 14 men, mean age 38.3, SD 11.6 years) underwent conventional MRI and DTI of the brain, 30 with 3 T and 10 with 1.5 T clinical scanners. ROI-based measurements for FA and ADC values were performed in five different anatomic locations of each hemisphere and in three locations within the corpus callosum. Mean values for FA and ADC for each region were calculated. Inter-observer variation of ROI measurements was evaluated by comparing the results of the two observers, intra-observer variation by repeated measurement of 10 subjects by both observers.
The FA values varied considerably between different regions. The highest values were found in the genu and splenium of the corpus callosum and the lowest in the corona radiata, respectively. In general, ADC values showed less variation; the highest values were found in the body of the corpus callosum and the lowest in the corona radiata. The reproducibility of both inter- and intra-observer measurements also varied regionally. The highest agreement was found for the corpus callosum and the lowest for the corona radiata and centrum semiovale.
In a normal adult population FA and ADC values of the brain white matter show regional variation. The repeatability of the ROI measurements also varies regionally. This regional variability must be acknowledged when these measurements are interpreted in clinical patients.
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.
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.
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.
Patterns of brain activation associated with a mental rotation task.
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.
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.
It is becoming increasingly clear that genetic variations account for a certain amount of variance in the acquisition and maintenance of different skills. Until now, several levels of genetic influences were examined, ranging from global heritability estimates down to the analysis of the contribution of single nucleotide polymorphisms (SNP) and variable number tandem repeats. In humans, the corticospinal motor system is essential to the acquisition of fine manual motor skills which require a finely tuned coordination of activity in distal forelimb muscles. Here we review recent brain mapping studies that have begun to explore the influence of functional genetic variation as well as mutations on function and structure of the human corticospinal motor system, and also the clinical implications of these studies. Transcranial magnetic stimulation of the primary motor hand area revealed a modulatory role of the common val66met polymorphism in the BDNF gene on corticospinal plasticity. Diffusion-sensitive magnetic resonance imaging has been employed to pinpoint subtle structural changes in corticospinal motor projections in individuals carrying a mutation in genes associated with motor neuron degeneration. These studies underscore the potential of non-invasive brain mapping techniques to characterize the genetic influence on the human corticospinal motor system.
Gender 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.
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.
Therefore, we postulated that male-to-female (MTF) transsexuals may show specific cerebral activation differing from their biological gender.
Cerebral activation patterns during viewing of erotic film excerpts in functional magnetic resonance imaging (fMRI).
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.
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.
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.
Previous postmortem anatomical studies have demonstrated differences between male and female in the size and shape of the splenium of the corpus callosum. The current study using the magnetic resonance imager compares the corpus callosum in 20 transsexuals and 40 controls to determine if the anatomic variance is related to anatomic sex or gender identity. No statistical differences were found in the cross-sectional areas of the entire corpus callosum, regardless of genetic sex or gender. However, the genetic males did have a larger whole-brain cross-sectional area. Also, even though there was a wide range of differences in shape and size in the splenium, the study found no significant differences between the sexes or between transsexual patients of either sex and the controls.
Previous studies have showed that lesions in the bed nucleus of the stria terminalis of experienced male rats impair some parameters of sexual behavior. The aim of this study was to examine the contribution of the medial posterior region of the bed nucleus of the stria terminalis (BSTMP), a sexually dimorphic region of this nucleus that pertains to the vomeronasal system, to the modulation of sexual behavior of the male rat. Small electrolytic bilateral lesions in the BSTMP were made in male heterosexual experienced and inexperienced rats. Sham lesioned animals were also tested as a control of the effects of the general surgical procedures. Behavioral tests were then performed to obtain standard measures of masculine sexual behavior. Our results indicate that the sexually experienced male rats with lesioned BSTMPs showed increases in the number of mounts and the number of intromissions and, consequently, in ejaculation latency. In contrast, the sexually naive male rats showed increases in first mount and intromission latencies and in ejaculation latency, but the latter occurred due to increases in the interintromission intervals. This group also showed low correlations between olfactory investigation of the anogenital area of the female and initiation and maintenance of copulatory behavior. The results suggest that sexual experience obtained in the very artificial conditions of laboratory tests could supply some of the cues provided by the BSTMP in the process of sensorial integration, which we hypothesize modulates the initiation and pacing of copulation. However, sexual experience does not apparently supply any other kinds of cues provided or processed in the BSTMP that are involved in modulating the elicitation of intromissions and ejaculations.
Transsexualism is considered to be the extreme end of the spectrum of gender identity disorders characterized by, among other things, a pursuit of sex reassignment surgery (SRS). The origins of transsexualism are still largely unclear. A first indication of anatomic brain differences between transsexuals and nontranssexuals has been found. Also, certain parental (rearing) factors seem to be associated with transsexualism. Some contradictory findings regarding etiology, psychopathology and success of SRS seem to be related to the fact that certain subtypes of transsexuals follow different developmental routes. The observations that psychotherapy is not helpful in altering a crystallized cross-gender identity and that certain transsexuals do not show severe psychopathology has led clinicians to adopt sex reassignment as a treatment option. In many countries, transsexuals are now treated according to the Standards of Care of the Harry Benjamin International Gender Dysphoria Association, a professional organization in the field of transsexualism. Research on postoperative functioning of transsexuals does not allow for unequivocal conclusions, but there is little doubt that sex reassignment substantially alleviates the suffering of transsexuals. However, SRS is no panacea. Psychotherapy may be needed to help transsexuals in adapting to the new situation or in dealing with issues that could not be addressed before treatment.
In an earlier study we demonstrated that 3 months of cross-sex hormone treatment clearly influenced cognitive functioning in transsexuals. The aims of the present study were to examine: (a) whether we could replicate these findings in a new group of transsexuals; (b) whether a similar pattern of change could be found for novel tasks, i.e. tasks, not used in the previous study, that measured closely related cognitive abilities; (c) whether the cognitive changes following cross-sex hormone treatment had stabilized after 3 months or continued to develop over a period of 1 year; and finally, (d) whether the effects were quickly reversible when the hormone treatment was temporarily stopped. Again a pronounced effect of androgen treatment was found on spatial ability in female-to-male transsexuals (FMs) over a period of one and a half years. As expected, untreated male-to-female transsexuals (MFs) had higher scores on visuo-spatial tasks than untreated FMs; after 3 months of cross-sex hormone treatment, the group difference had disappeared, while after about 10 months of hormone treatment, the sex difference was reversed. These effects did not disappear after termination of cross-sex hormone therapy for a period of 5 weeks, but continued to change slightly in the same direction. Earlier findings of an opposite effect of cross-sex hormones on verbal fluency (i.e. MFs improved and FMs deteriorated after 3 months of cross-sex hormone treatment) were not replicated in this study, nor did we find an hormonal influence on other cognitive functions. This study shows that testosterone had an enhancing, and not quickly reversible effect, on spatial ability performance, but no deteriorating effect on verbal fluency in adult women (FMs). In contrast, anti-androgen treatment in combination with estrogen therapy had no declining effect on spatial ability, nor an enhancing effect on verbal fluency in adult men (MFs).
The anatomical pathways for processing of odorous stimuli include the olfactory nerve projection to the olfactory bulb, the trigeminal nerve projection to somatosensory and insular cortex, and the projection from the accessory olfactory bulb to the hypothalamus. In the majority of tetrapods, the sex-specific effects of pheromones on reproductive behavior is mediated via the hypothalamic projection. However, the existence of this projection in humans has been regarded as improbable because humans lack a discernable accessory olfactory bulb. Here, we show that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.
An automated method for segmenting magnetic resonance head images into brain and non-brain has been developed. It is very robust and accurate and has been tested on thousands of data sets from a wide variety of scanners and taken with a wide variety of MR sequences. The method, Brain Extraction Tool (BET), uses a deformable model that evolves to fit the brain's surface by the application of a set of locally adaptive model forces. The method is very fast and requires no preregistration or other pre-processing before being applied. We describe the new method and give examples of results and the results of extensive quantitative testing against "gold-standard" hand segmentations, and two other popular automated methods.