Gender detransition: A critical review of the literature.

Gender detransition is the act of stopping or reversing the social, medical, and/or administrative changes achieved during a gender transition process. It is an emerging phenomenon of significant clinical and social interest.

Destransición de género: Una revisión crítica de la literatura / Gender detransition: a critical review of the literature

Introducción. La destransición de género es el acto de detenero revertir los cambios sociales, médicos y/o administrativos conseguidos durante un proceso de transición de género. Se trata de un fenómeno emergente de gran interés a nivel clínico y social. Método. Se condujo una búsqueda sistemática en siete bases de datos entre 2010 y 2022, se rastrearon manualmente las referencias de los artículos y se consultaron libros especializados. Se realizó un análisis cuantitativo y de contenido. Resultados. Se incluyeron 138 registros, 37% correspondientes a estudios empíricos y 38,4% publicados en 2021. Se identifican al menos ocho términos para hacer referencia a la destransición, con diferencias en sus definiciones. La prevalencia difiere en función del criterio utilizado, siendo menor para la destransición/arrepentimiento (0-13,1%) que para la descontinuación de la asistencia/tratamiento médico (1,9%-29,8%),y menor para la destransición/arrepentimiento tras cirugía (0-2,4%) que para la destransición/arrepentimiento tras tratamiento hormonal (0-9,8%). Se describen más de 50 factores psicológicos, médicos y socioculturales que influyen en la decisión de destransicionar, así como 16 factores predictores/asociados a la destransición. No se encuentran guías de abordaje sanitario ni legislativo. Los debates actuales se centran en los interrogantes sobre la naturaleza de la disforia de género y el desarrollo de la identidad, el papel de los profesionales con respecto al acceso a los tratamientos médicos y el impacto de las destransiciones sobre la futura accesibilidad a dichos tratamientos. Conclusiones. La destransición de género es una realidad compleja, heterogénea, poco estudiada y escasamente comprendida. Se requiere un abordaje y estudio sistemático que permita comprender su prevalencia real, implicaciones y manejo a nivel sanitario. (AU)

Introduction. Gender detransition is the act of stoppingor reversing the social, medical, and/or administrative changesachieved during a gender transition process. It is an emergingphenomenon of significant clinical and social interest.Methods. We systematically searched seven databasesbetween 2010 and 2022, manually traced article references,and consulted specialized books. Quantitative and contentanalyses were carried out.Results. We included 138 registers, 37% of which were empirical studies and 38.4% of which were published in 2021. Atleast eight terms related to detransition were identified, withdifferences in their definitions. Prevalence estimates differ according to the criteria used, being lower for detransition/regret (0-13.1%) than for discontinuation of care/medical treatment (1.9%-29.8%), and for detransition/regret after surgery(0-2.4%) than for detransition/regret after hormonal treatment (0-9.8%). More than 50 psychological, medical, and sociocultural factors influencing the decision to detransition and16 predictors/associated factors are described. No health orlegal guidelines are found. Current debates focus on the nature of gender dysphoria and identity development, the role ofprofessionals in accessing medical treatments, and the impactof detransition on future access to these treatments.Conclusions. Gender detransition is a complex, heterogeneous, under-researched, and poorly understood reality. Asystematic study and approach to the topic is needed to understand its prevalence, implications, and management from a healthcare perspective. (AU)

Whole-brain dynamics differentiate among cisgender and transgender individuals.

How the brain represents gender identity is largely unknown, but some neural differences have recently been discovered. We used an intrinsic ignition framework to investigate whether there are gender differences in the propagation of neural activity across the whole-brain and within resting-state networks. Studying 29 trans men and 17 trans women with gender incongruence, 22 cis women, and 19 cis men, we computed the capability of a given brain area in space to propagate activity to other areas (mean-ignition), and the variability across time for each brain area (node-metastability). We found that both measurements differentiated all groups across the whole brain. At the network level, we found that compared to the other groups, cis men showed higher mean-ignition of the dorsal attention network and node-metastability of the dorsal and ventral attention, executive control, and temporal parietal networks. We also found higher mean-ignition values in cis men than in cis women within the executive control network, but higher mean-ignition in cis women than cis men and trans men for the default mode. Node-metastability was higher in cis men than cis women in the somatomotor network, while both mean-ignition and node-metastability were higher for cis men than trans men in the limbic network. Finally, we computed correlations between these measurements and a body image satisfaction score. Trans men's dissatisfaction as well as cis men's and cis women's satisfaction toward their own body image were distinctively associated with specific networks in each group. Overall, the study of the whole-brain network dynamical complexity discriminates gender identity groups, functional dynamic approaches could help disentangle the complex nature of the gender dimension in the brain.

Brain connectivity dynamics in cisgender and transmen people with gender incongruence before gender affirmative hormone treatment.

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.

Cardiovascular Risk Associated With Gender Affirming Hormone Therapy in Transgender Population.

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.

Epigenetics Is Implicated in the Basis of Gender Incongruence: An Epigenome-Wide Association Analysis.

INTRODUCTION: The main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population. METHODS: A global CpG (cytosine-phosphate-guanine) methylation analysis was performed on blood from 16 transgender people before GAHT vs. 16 cisgender people using the Illumina© Infinium Human Methylation 850k BeadChip, after bisulfite conversion. Changes in the DNA methylome in cisgender vs. transgender populations were analyzed with the Partek® Genomics Suite program by a 2-way ANOVA test comparing populations by group and their sex assigned at birth. RESULTS: The principal components analysis (PCA) showed that both populations (cis and trans) differ in the degree of global CpG methylation prior to GAHT. The 2-way ANOVA test showed 71,515 CpGs that passed the criterion FDR p < 0.05. Subsequently, in male assigned at birth population we found 87 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2) of which 22 were located in islands. The most significant CpGs were related to genes: WDR45B, SLC6A20, NHLH1, PLEKHA5, UBALD1, SLC37A1, ARL6IP1, GRASP, and NCOA6. Regarding the female assigned at birth populations, we found 2 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2), but none were located in islands. One of these CpGs, related to the MPPED2 gene, is shared by both, trans men and trans women. The enrichment analysis showed that these genes are involved in functions such as negative regulation of gene expression (GO:0010629), central nervous system development (GO:0007417), brain development (GO:0007420), ribonucleotide binding (GO:0032553), and RNA binding (GO:0003723), among others. STRENGTHS AND LIMITATIONS: It is the first time that a global CpG methylation analysis has been carried out in a population with gender incongruence before GAHT. A prospective study before/during GAHT would provide a better understanding of the influence of epigenetics in this process. CONCLUSION: The main finding of this study is that the cis and trans populations have different global CpG methylation profiles prior to GAHT. Therefore, our results suggest that epigenetics may be involved in the etiology of gender incongruence.

Implications of the Estrogen Receptor Coactivators SRC1 and SRC2 in the Biological Basis of Gender Incongruence.

INTRODUCTION: Brain sexual differentiation results from the effects of sex steroids on the developing brain. The presumptive route for brain masculinization is the direct induction of gene expression via activation of the estrogen receptors α and ß and the androgen receptor through their binding to ligands and to coactivators, regulating the transcription of multiple genes in a cascade effect. AIM: To analyze the implication of the estrogen receptor coactivators SRC-1, SRC-2, and SRC-3 in the genetic basis of gender incongruence. MAIN OUTCOME MEASURES: Analysis of 157 polymorphisms located at the estrogen receptor coactivators SRC-1, SRC-2, and SRC-3, in 94 transgender versus 94 cisgender individuals. METHOD: Using SNPStats software, the allele and genotype frequencies were analyzed by χ2, the strength of the association was measured by binary logistic regression, estimating the odds ratio for each genotype. Measurements of linkage disequilibrium and haplotype frequencies were also performed. RESULTS: We found significant differences at level P < .05 in 8 polymorphisms that correspond to 5.09% of the total. Three were located in SRC-1 and 5 in SRC-2. The odds ratio analysis showed significant differences at level P < .05 for multiple patterns of inheritance. The polymorphisms analyzed were in linkage disequilibrium. The SRC-1 haplotypes CGA and CGG (global haplotype association P < .009) and the SRC-2 haplotypes GGTAA and GGTAG (global haplotype association P < .005) were overrepresented in the transgender population. CONCLUSION: The coactivators SRC-1 and SRC-2 could be considered as candidates for increasing the list of potential genes for gender incongruence. Ramírez KDV, Fernández R, Delgado-Zayas E, et al. Implications of the Estrogen Receptor Coactivators SRC1 and SRC2 in the Biological Basis of Gender Incongruence. Sex Med 2021;9:100368.

The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group.

BACKGROUND: In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. AIM: To examine the neurobiology of transgender persons in a large sample. METHODS: Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. OUTCOMES: Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS: Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. CLINICAL TRANSLATION: The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. STRENGTHS AND LIMITATIONS: While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION: Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype. Mueller SC, Guillamon A, Zubiaurre-Elorza L, et al. The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group. J Sex Med 2021;18:1122-1129.

Psychopathological symptoms in Spanish subjects with gender dysphoria. A cross-sectional study.

BACKGROUND: Most people with gender dysphoria have to face various stressful conditions, which make them more vulnerable to the development of psychopathological symptoms. AIMS: The main goal was to compare psychopathological symptoms between individuals with gender dysphoria and those from the general population. Other secondary aims were to determine if there were differences between gender [male to females (MtFs) and female to males (FtMs)] and also according to cross-sex hormone therapy. METHOD: Symptom Checklist 90 Revised (SCL-90-R) questionnaire was administered to a sample of 205 subjects with gender dysphoria (MtFs = 129 and FtMs = 76). The control group included 530 individuals from the general population who took part in the Spanish validation of the SCL-90-R questionnaire. RESULTS: Overall, individuals with gender dysphoria had higher scores on all SCL-90-R dimensions than the general population, except in the dimension of somatization, in which MtF and FtM subjects scored statistically higher than control males but not than control females. The mean scores of all dimensions except Depression (mean score of 1.17) were below 1, that is, between 0 (not at all) and 1 (occasionally). All dimensions did not differ when comparing MtFs and FtMs nor when comparing gender dysphoric subjects with or without cross-sex hormonal therapy. CONCLUSIONS: The results suggested that most subjects with gender dysphoria attending a gender unit reported higher levels of psychopathology than the general population. However, the scores were indicative of the lack of any clinically relevant psychopathological symptoms.

Investigación española en disforia de género: una revisión de más de 20 años de literatura biomédica / Spanish research in gender dysphoria: a systematic review of more than 20 years of biomedical literature

OBJETIVO: Realizar un análisis bibliométrico y de contenido de la investigación biomédica española sobre disforia de género basado en una revisión de la literatura. MÉTODO: Se realizó una búsqueda en cinco bases de datos internacionales, cuatro nacionales, y dos plataformas editoriales, con la palabra clave "disforia de género" y términos relacionados. Los resultados se combinaron con España y con el nombre de las ciudades españolas con hospital. Se seleccionaron los artículos generados desde las Unidades de Identidad de Género (UIG). El número de citaciones se evaluó mediante el Science Citation Index (SCI) y Google Scholar. RESULTADO: Un total de 179 trabajos fueron incluidos. La producción presenta un incremento progresivo desde 1998 hasta 2015 y un ligero decremento posterior. El 34,6% están publicados en inglés, el 45,8% están basados en casuística de usuarios atendidos, y la temática más frecuente es la psicología y salud mental (58,1%). Los 75 artículos de revistas incluidas en el SCI han recibido 1.252 citas, y los 152 artículos incluidos en Google Scholar, 3.105 citas. La mayor media de citas SCI por artículo corresponde a los publicados en inglés (22,2), basados en casuística (21,1), ámbito de la neuroimagen (52), y generados desde la UIG de Cataluña (25,7). CONCLUSIONES: La producción científica española sobre disforia de género generada desde las UIG ha tenido un cre-cimiento progresivo, abarca una amplia temática, incluye un elevado número de estudios basados en el análisis de la casuística de la población atendida, y las citaciones recibidas reflejan un impacto en la comunidad científica y un liderazgo internacional en algunas áreas como la neuroimagen

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 de-crease 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

[New care models for transgender people in the Spanish Health System: demands, controversies and reflections.] / Nuevos modelos de atención sanitaria para las personas transgénero en el Sistema Sanitario Español: demandas, controversias y reflexiones.

Health care for transgender people in Spain has been progressively established since 1999 when the first multidisciplinary unit for the treatment of sex reassignment was created in Andalusia. In this document, the social changes, the demands and debates of users and professionals, the new models of health care for trans people, and reflections on the current situation, have been analysed. The social openness in Spain regarding sexual and gender diversity has evolved quite positively. The health demands of the transgender users are not uniform and do not always match with the criteria of the professionals. In some Spanish regions, health care is distancing itself from the internationally recommended multidisciplinary model. The new healthcare models have been established under the aegis of primary care and/or endocrinologist in the area, without a required psychological assessment. The main contributing factors for this change of model have been the pressure from some associations with demands for "depathologization" and "decentralization". The professionals of gender units, while recognizing the need for a broader vision of trans reality, warn of the risk of treating trans people without the involvement of mental health specialists or by professionals in proximity with little experience. Moreover, the decentralization would not allow acting on large cohorts, which hinders the advance of knowledge and contrasted evaluations with neighbouring countries. In summary, the new health models, although intended to facilitate care through proximity, do not guarantee improvements in quality and difficult to make a comparative evaluation of the results.

La atención sanitaria a las personas transgénero en España se ha establecido de manera progresiva desde 1999, año en que Andalucía crea la primera unidad multidisciplinar para el tratamiento integral de la reasignación de sexo. Este documento analiza los cambios sociales, las demandas y debates entre usuarios y profesionales y los nuevos modelos de atención sanitaria, y también plantea reflexiones sobre la situación actual. La apertura social en España en la concepción de la diversidad sexual y de género es bastante favorable. Las demandas de los usuarios no son uniformes y no siempre coinciden con los criterios de los profesionales. En algunas comunidades autónomas la asistencia sanitaria se está distanciando del modelo recomendado internacionalmente, que basa la atención en equipos especializados o Unidades de Identidad de Género (UIG). Estos nuevos modelos centran la asistencia en la Atención Primaria, además de en endocrinólogos y pediatras de área sin una evaluación coordinada con Salud Mental. Los principales factores contribuyentes al cambio reciente han sido las demandas desde algunas asociaciones de "despatologización" y "descentralización". Estos nuevos modelos centran la asistencia en la Atención Primaria, además de en endocrinólogos y pediatras de área sin una evaluación coordinada con Salud Mental. Los profesionales que integran las unidades de género, si bien reconocen la necesidad de una visión amplia de la realidad transgénero, alertan del riesgo que supone tratar a personas trans sin una colaboración de especialistas en Salud Mental o por profesionales de área con escasa experiencia. Además, anticipan que la descentralización no facilita el estudio de grandes cohortes, dificultando el avance del conocimiento y la evaluación contrastada con países del entorno. En resumen, los nuevos modelos sanitarios, aunque ofrecen la atención en proximidad, no garantizan mejoras en la calidad ni promueven el análisis comparado de los resultados.

Effects of adult male rat feminization treatments on brain morphology and metabolomic profile.

Body feminization, as part of gender affirmation process of transgender women, decreases the volume of their cortical and subcortical brain structures. In this work, we implement a rat model of adult male feminization which reproduces the results in the human brain and allows for the longitudinal investigation of the underlying structural and metabolic determinants in the brain of adult male rats undergoing feminization treatments. Structural MRI and Diffusion Tensor Imaging (DTI) were used to non-invasively monitor in vivo cortical brain volume and white matter microstructure over 30 days in adult male rats receiving estradiol (E2), estradiol plus cyproterone acetate (CA), an androgen receptor blocker and antigonadotropic agent (E2 + CA), or vehicle (control). Ex vivo cerebral metabolic profiles were assessed by 1H High Resolution Magic Angle Spinning NMR (1H HRMAS) at the end of the treatments in samples from brain regions dissected after focused microwave fixation (5 kW). We found that; a) Groups receiving E2 and E2 + CA showed a generalized bilateral decrease in cortical volume; b) the E2 + CA and, to a lesser extent, the E2 groups maintained fractional anisotropy values over the experiment while these values decreased in the control group; c) E2 treatment produced increases in the relative concentration of brain metabolites, including glutamate and glutamine and d) the glutamine relative concentration and fractional anisotropy were negatively correlated with total cortical volume. These results reveal, for the first time to our knowledge, that the volumetric decreases observed in trans women under cross-sex hormone treatment can be reproduced in a rat model. Estrogens are more potent drivers of brain changes in male rats than anti-androgen treatment.

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen.

BACKGROUND: Brain sexual differentiation is a process that results from the effects of sex steroids on the developing brain. Evidence shows that epigenetics plays a main role in the formation of enduring brain sex differences and that the estrogen receptor α (ESR1) is one of the implicated genes. AIM: To analyze whether the methylation of region III (RIII) of the ESR1 promoter is involved in the biological basis of gender dysphoria. METHODS: We carried out a prospective study of the CpG methylation profile of RIII (-1,188 to -790 bp) of the ESR1 promoter using bisulfite genomic sequencing in a cisgender population (10 men and 10 women) and in a transgender population (10 trans men and 10 trans women), before and after 6 months of gender-affirming hormone treatment. Cisgender and transgender populations were matched by geographical origin, age, and sex. DNAs were treated with bisulfite, amplified, cloned, and sequenced. At least 10 clones per individual from independent polymerase chain reactions were sequenced. The analysis of 671 bisulfite sequences was carried out with the QUMA (QUantification tool for Methylation Analysis) program. OUTCOMES: The main outcome of this study was RIII analysis using bisulfite genomic sequencing. RESULTS: We found sex differences in RIII methylation profiles in cisgender and transgender populations. Cismen showed a higher methylation degree than ciswomen at CpG sites 297, 306, 509, and at the total fragment (P ≤ .003, P ≤ .026, P ≤ .001, P ≤ .006). Transmen showed a lower methylation level than trans women at sites 306, 372, and at the total fragment (P ≤ .0001, P ≤ .018, P ≤ .0107). Before the hormone treatment, transmen showed the lowest methylation level with respect to cisgender and transgender populations, whereas transwomen reached an intermediate methylation level between both the cisgender groups. After the hormone treatment, transmen showed a statistically significant methylation increase, whereas transwomen showed a non-significant methylation decrease. After the hormone treatment, the RIII methylation differences between transmen and transwomen disappeared, and both transgender groups reached an intermediate methylation level between both the cisgender groups. CLINICAL IMPLICATIONS: Clinical implications in the hormonal treatment of trans people. STRENGTHS & LIMITATIONS: Increasing the number of regions analyzed in the ESR1 promoter and increasing the number of tissues analyzed would provide a better understanding of the variation in the methylation pattern. CONCLUSIONS: Our data showed sex differences in RIII methylation patterns in cisgender and transgender populations before the hormone treatment. Furthermore, before the hormone treatment, transwomen and transmen showed a characteristic methylation profile, different from both the cisgender groups. But the hormonal treatment modified RIII methylation in trans populations, which are now more similar to their gender. Therefore, our results suggest that the methylation of RIII could be involved in gender dysphoria. Fernández R, Ramírez K, Gómez-Gil E, et al. Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen. J Sex Med 2020;17:1795-1806.

Data for functional MRI connectivity in transgender people with gender incongruence and cisgender individuals.

We provide T2*-weighted and T1-weighted images acquired on a 3T MRI scanner obtained from 17 transwomen and 29 transmen with gender incongruence; and 22 ciswomen and 19 cismen that identified themselves to the sex assigned at birth. Data from three different techniques that describe global and regional connectivity differences within functional resting-state networks in transwomen and transmen with early-in-life onset gender incongruence are provided: (1) we obtained spatial maps from data-driven independent component analysis using the melodic tool from FSL software; (2) we provide the functional networks interactions of two functional atlases' seeds from a seed-to-seed approach; (3) and global graph-theoretical metrics such as the smallworld organization, and the segregation and integration properties of the networks. Interpretations of the present dataset can be found in the original article, doi:10.1016/j.neuroimage.2020.116613[1]. The original and processed nifti images are available in Mendeley datasets. In addition, correlation matrices for the seed-to-seed and graph-theory analyses as well as the graph-theoretical measures were made available in Matlab files. Finally, we present supplementary information for the original article.

Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence.

INTRODUCTION: Gender incongruence defines a state in which individuals feel discrepancy between the sex assigned at birth and their gender. Some of these people make a social transition from male to female (trans women) or from female to male (trans men). By contrast, the word cisgender describes a person whose gender identity is consistent with their sex assigned at birth. AIM: To analyze the implication of the estrogen receptor α gene (ESR1) in the genetic basis of gender incongruence. MAIN OUTCOME MEASURES: Polymorphisms rs9478245, rs3138774, rs2234693, rs9340799. METHOD: We carried out the analysis of 4 polymorphisms located at the promoter of the ESR1 gene (C1 = rs9478245, C2 = rs3138774, C3 = rs2234693, and C4 = rs9340799) in a population of 273 trans women, 226 trans men, and 537 cis gender controls. For SNP polymorphisms, the allele and genotype frequencies were analyzed by χ2 test. The strength of the SNP associations with gender incongruence was measured by binary logistic regression. For the STR polymorphism, the mean number of repeats were analyzed by the Mann-Whitney U test. Measurement of linkage disequilibrium and haplotype frequencies were also performed. RESULTS: The C2 median repeats were shorter in the trans men population. Genotypes S/S and S/L for the C2 polymorphism were overrepresented in the trans men group (P = .012 and P = .003 respectively). We also found overtransmission of the A/A genotype (C4) in the trans men population (P = .017), while the A/G genotype (C4) was subrepresented (P = .009]. The analyzed polymorphisms were in linkage disequilibrium. In the trans men population, the T(C1)-L(C2)-C(C3)-A(C4) haplotype was overrepresented (P = .019) while the T(C1)-L(C2)-C(C3)-G(C4) was subrepresented (P = .005). CONCLUSION: The ESR1 is associated with gender incongruence in the trans men population. Fernández R, Delgado-Zayas E,RamírezK, et al. Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence. Sex Med 2020;8:490-500.

Brain network interactions in transgender individuals with gender incongruence.

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.

Spanish research in gender dysphoria: A review of more than 20 years of biomedical literature.

To provide a bibliometric and contents analyses of the Spanish research in the field of gender dysphoria based on a literature review.

Nuevos modelos de atención sanitaria para las personas transgénero en el sistema sanitario español: demandas, controversias y reflexiones / New care models for transgender people in the Spanish Health System: demands, controversies and reflections

La atención sanitaria a las personas transgénero en España se ha establecido de manera progresiva desde 1999, año en que Andalucía crea la primera unidad multidisciplinar para el tratamiento integral de la reasignación de sexo. Este documento analiza los cambios sociales, las demandas y debates entre usuarios y profesionales y los nuevos modelos de atención sanitaria, y también plantea reflexiones sobre la situación actual. La apertura social en España en la concepción de la diversidad sexual y de género es bastante favorable. Las demandas de los usuarios no son uniformes y no siempre coinciden con los criterios de los profesionales. En algunas comunidades autónomas la asistencia sanitaria se está distanciando del modelo recomendado internacionalmente, que basa la atención en equipos especializados o Unidades de Identidad de Género (UIG). Estos nuevos modelos centran la asistencia en la Atención Primaria, además de en endocrinólogos y pediatras de área sin una evaluación coordinada con Salud Mental. Los principales factores contribuyentes al cambio reciente han sido las demandas desde algunas asociaciones de "despatologización" y "descentralización". Estos nuevos modelos centran la asistencia en la Atención Primaria, además de en endocrinólogos y pediatras de área sin una evaluación coordinada con Salud Mental. Los profesionales que integran las unidades de género, si bien reconocen la necesidad de una visión amplia de la realidad transgénero, alertan del riesgo que supone tratar a personas trans sin una colaboración de especialistas en Salud Mental o por profesionales de área con escasa experiencia. Además, anticipan que la descentralización no facilita el estudio de grandes cohortes, dificultando el avance del conocimiento y la evaluación contrastada con países del entorno. En resumen, los nuevos modelos sanitarios, aunque ofrecen la atención en proximidad, no garantizan mejoras en la calidad ni promueven el análisis comparado de los resultados

Health care for transgender people in Spain has been progressively established since 1999 when the first multidisciplinary unit for the treatment of sex reassignment was created in Andalusia. In this document, the social changes, the demands and debates of users and professionals, the new models of health care for trans people, and reflections on the current situation, have been analysed. The social openness in Spain regarding sexual and gender diversity has evolved quite positively. The health demands of the transgender users are not uniform and do not always match with the criteria of the professionals. In some Spanish regions, health care is distancing itself from the internationally recommended multidisciplinary model. The new healthcare models have been established under the aegis of primary care and/or endocrinologist in the area, without a required psychological assessment. The main contributing factors for this change of model have been the pressure from some associations with demands for "depathologization" and "decentralization". The professionals of gender units, while recognizing the need for a broader vision of trans reality, warn of the risk of treating trans people without the involvement of mental health specialists or by professionals in proximity with little experience. Moreover, the decentralization would not allow acting on large cohorts, which hinders the advance of knowledge and contrasted evaluations with neighbouring countries. In summary, the new health models, although intended to facilitate care through proximity, do not guarantee improvements in quality and difficult to make a comparative evaluation of the results

Patterns of alcohol, tobacco, and illicit drug use among transsexuals. / Patrones de consumo de alcohol, tabaco y drogas ilegales en personas transexuales.

This study evaluated the patterns of substance use in a large sample of male-to-female (MtoF) and female-to-male (FtoM) transsexuals. A total of 251 transsexual subjects (163 MtoF and 88 FtoM), attended in the Catalonia Gender Unit, completed self-administrated questionnaires on consumption of alcohol, tobacco, cannabis, cocaine, opioids, and designer drugs. Results were compared with the general population in Catalonia using data from the National Health Service (EDADES 2013 study). Current consumption of alcohol (70.1%), tobacco (46.2%), and cannabis (16.3%) among transsexuals was similar when compared with men (72.1%, 42.1%, 12.8%) and increased when compared with women (57.6%, 35.2%, 5%); the consumption between MtoF and FtoM subgroups was similar.  The use of cocaine was almost ten times more prevalent in the MtoF subgroup than in the FtoM subgroup (1.1%), and in general population (less than 1%).  Only a few reported uses of opioids and designer drugs. In conclusion, the substance use among transsexuals, except for the use of cocaine, was similar between MtoF and FtoM subgroups, and resembled the consumption prevalence among men in the general population. The proportion of cocaine consumers in the MtoF subgroup was up to ten times higher than in other subgroups.

Este estudio evalúa los patrones de consumo de sustancias en personas transexuales de hombre a mujer (H-M) y de mujer a hombre (M-H). Un total de 251 personas transexuales (163 H-M y 88 M-H), atendidas en la Unidad de Identidad de Género de Cataluña, completaron un cuestionario autoadministrado sobre el consumo de alcohol, tabaco, cannabis, cocaína, opiáceos y drogas de diseño. Los resultados se compararon con datos del Servicio Nacional de Salud en población general en Cataluña (estudio EDADES 2013). La prevalencia del consumo de alcohol (70,1%), tabaco (46,2%) y cannabis (16,3%) actual en el total de personas transexuales de ambos sexos fue similar al de hombres en población general (72,1%, 42,1%, 12,8%) y mayor que la prevalencia en mujeres (57,6%, 35,2%, 5%); no se encontraron diferencias en dicho consumo entre H-M y M-H. El consumo de cocaína en H-M (9,8%) fue casi diez veces más prevalente que en el subgrupo M-H (1,1%) y que en ambos sexos en población general (menor del 1%). Sólo unos pocos referían consumo de opiáceos y drogas de diseño. En conclusión, el patrón de consumo de sustancias en personas transexuales, excepto para la cocaína, es similar entre ambos sexos, y se asemeja al patrón de consumo masculino en población general. El consumo de cocaína es hasta diez veces mayor en el grupo de mujeres transexuales (H-M) con respecto a los otros grupos.

Patrones de consumo de alcohol, tabaco y drogas ilegales en personas transexuales / Patterns of alcohol, tobacco, and illicit drug use among transsexuals

Este estudio evalúa los patrones de consumo de sustancias en personas transexuales de hombre a mujer (H-M) y de mujer a hombre (M-H). Un total de 251 personas transexuales (163 H-M y 88 M-H), atendidas en la Unidad de Identidad de Género de Cataluña, completaron un cuestionario autoadministrado sobre el consumo de alcohol, tabaco, cannabis, cocaína, opiáceos y drogas de diseño. Los resultados se compararon con datos del Servicio Nacional de Salud en población general en Cataluña (estudio EDADES 2013). La prevalencia del consumo de alcohol (70,1%), tabaco (46,2%) y cannabis (16,3%) actual en el total de personas transexuales de ambos sexos fue similar al de hombres en población general (72,1%, 42,1%, 12,8%) y mayor que la prevalencia en mujeres (57,6%, 35,2%, 5%); no se encontraron diferencias en dicho consumo entre H-M y M-H. El consumo de cocaína en H-M (9,8%) fue casi diez veces más prevalente que en el subgrupo M-H (1,1%) y que en ambos sexos en población general (menor del 1%). Sólo unos pocos referían consumo de opiáceos y drogas de diseño. En conclusión, el patrón de consumo de sustancias en personas transexuales, excepto para la cocaína, es similar entre ambos sexos, y se asemeja al patrón de consumo masculino en población general. El consumo de cocaína es hasta diez veces mayor en el grupo de mujeres transexuales (H-M) con respecto a los otros grupos

This study evaluated the patterns of substance use in a large sample of male-to-female (MtoF) and female-to-male (FtoM) transsexuals. A total of 251 transsexual subjects (163 MtoF and 88 FtoM), attended in the Catalonia Gender Unit, completed self-administrated questionnaires on consumption of alcohol, tobacco, cannabis, cocaine, opioids, and designer drugs. Results were compared with the general population in Catalonia using data from the National Health Service (EDADES 2013 study). Current consumption of alcohol (70.1%), tobacco (46.2%), and cannabis (16.3%) among transsexuals was similar when compared with men (72.1%, 42.1%, 12.8%) and increased when compared with women (57.6%, 35.2%, 5%); the consumption between MtoF and FtoM subgroups was similar. The use of cocaine was almost ten times more prevalent in the MtoF subgroup than in the FtoM subgroup (1.1%), and in general population (less than 1%). Only a few reported uses of opioids and designer drugs. In conclusion, the substance use among transsexuals, except for the use of cocaine, was similar between MtoF and FtoM subgroups, and resembled the consumption prevalence among men in the general population. The proportion of cocaine consumers in the MtoF subgroup was up to ten times higher than in other subgroups