CBLL1 is hypomethylated and correlates with cortical thickness in transgender men before gender affirming hormone treatment.

Gender identity refers to the consciousness of being a man, a woman or other condition. Although it is generally congruent with the sex assigned at birth, for some people it is not. If the incongruity is distressing, it is defined as gender dysphoria (GD). Here, we measured whole-genome DNA methylation by the Illumina © Infinium Human Methylation 850k array and reported its correlation with cortical thickness (CTh) in 22 transgender men (TM) experiencing GD versus 25 cisgender men (CM) and 28 cisgender women (CW). With respect to the methylation analysis, TM vs. CW showed significant differences in 35 CpGs, while 2155 CpGs were found when TM vs. CM were compared. With respect to correlation analysis, TM showed differences in methylation of CBLL1 and DLG1 genes that correlated with global and left hemisphere CTh. Both genes were hypomethylated in TM compared to the cisgender groups. Early onset TM showed a positive correlation between CBLL1 and several cortical regions in the frontal (left caudal middle frontal), temporal (right inferior temporal, left fusiform) and parietal cortices (left supramarginal and right paracentral). This is the first study relating CBLL1 methylation with CTh in transgender persons and supports a neurodevelopmental hypothesis of gender identity.

Testosterone administration affects 1H-MRS metabolite spectra in transgender men.

BACKGROUND: Recently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain endophenotype in people with gender dysphoria (GD). However, despite mounting neuroimaging work, brain gender differences and effects of gender-affirming hormone therapy (GAHT) at the metabolite level remain understudied. METHODS: Thirty-one transgender men (TM) before and after testosterone administration (7.7 months ± 3.5 months), relative to 30 cisgender men (CM) and 35 cisgender women (CW) underwent magnetic resonance spectroscopy (1H-MRS) at two time points. Two brain regions were assessed, i.e. the lateral parietal cortex and the amygdala/anterior hippocampus. Associated metabolites that were measured include N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), glutamate and glutamine (Glx), myo-inositol (mI), glycine (Gly) and their respective ratios. RESULTS: A critical time by group interaction revealed an effect of GAHT in the lateral parietal cortex of TM. MI+Gly/Cr ratios decreased upon initiation of GAHT. In addition, NAA/Cr and Cho/Cr ratios were lower in CW when compared to CM in the lateral parietal cortex. Glx levels and Glx/Cr ratios in TM differed from those in CW in the amygdala/anterior hippocampus. Interestingly, pubertal age of onset of gender dysphoria (i.e. GD) in TM differentially affected testosterone-mediated effects on Cr concentration and NAA/Cr ratios when compared to childhood and adult GD onset in the amygdala/anterior hippocampus. CONCLUSION: This 1H-MRS study demonstrated that testosterone administration shifts mI+Gly/Cr ratios in the parietal cortex. In the amygdala/anterior hippocampus, modulation of metabolite concentrations by age of onset of GD is suggestive for a possible developmental trend.

Gender minority stress in transgender people: a major role for social network.

BACKGROUND: Gender minority individuals, on average, experience higher rates of mental health problems. Mounting work suggests that gender minority stress (GMS) contributes to mental health outcomes in transgender/gender-nonconforming individuals. AIM: We assessed whether GMS decreased in transgender people after initiating gender-affirming hormone therapy (GAHT), and we identified social predictors and hormonal associations for GMS at 2 time points. METHODS: GMS was surveyed through self-report questionnaires tapping into proximal and distal stressors and coping constructs following the minority stress framework. Eighty-five transgender persons wishing to undertake hormonal interventions were assessed prospectively at start of GAHT and after 7.7 ± 3.5 months (mean ± SD). Sixty-five cisgender persons served as a control group. OUTCOMES: (1) Proximal stressors were surveyed by the Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Stigma Consciousness Questionnaire, and Perceived Stress Scale; (2) distal stressors by the Everyday Discrimination Scale; and (3) coping constructs by the Resilience Scale, social network, social standing, and Marlowe Crowne Social Desirability Scale. RESULTS: Transgender people experienced higher rates of proximal stressors (Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Perceived Stress Scale) and had lower protective factors (social standing) prior to and during GAHT than cisgender people. Social network and resilience were lower in transgender people relative to cisgender peers only at baseline. Prospectively, decreasing trait anxiety was observed in transgender people. Social factors were adequate predictors of multiple GMS constructs. Specifically, a major role for social network emerged. As for hormonal associations, only serum estradiol levels in transgender women with GAHT were negatively associated with trait anxiety and suicidal thoughts/attempts but positively with resilience and social desirability. CLINICAL IMPLICATIONS: Stimulating a social environment supportive of diverse identities, particularly by investing in social networks as a resource for resilience, is likely to alleviate GMS. STRENGTHS AND LIMITATIONS: Longer duration of interventions with sex steroid treatment, with continued resilience-enhancing strategies, is needed to observe further alleviation of GMS in transgender persons. Also, objective and subjective GMS identification with heteronormative attitudes and beliefs should be surveyed for good measure when assessing GMS. CONCLUSION: Transgender people experienced more GMS throughout study visits than cisgender people did. With a relatively short period of GAHT, some significant changes in and predictors for experienced GMS emerged.

Gender-affirming hormonal treatment changes neural processing of emotions in trans men: An fMRI study.

BACKGROUND: Some transgender people desire a transition through gender-affirming hormone treatment (GAHT). To date, it is unknown how GAHT changes emotion perception in transgender people. METHODS: Thirty transgender men (TM), 30 cisgender men (CM), and 35 cisgender women (CW) underwent 3 Tesla functional magnetic resonance imaging (fMRI) while passively viewing emotional faces (happy, angry, surprised faces) at two timepoints (T0 and T1). At T0 all participants were hormone-naïve, while TM immediately commenced testosterone supplementation at T0. The second scanning session (T1) occurred after 6-10 months of GAHT in TM. All 3 groups completed both T0 and T1 RESULTS: GAHT in TM shifted the neural profile whilst processing emotions from a sex-assigned at birth pattern at T0 (similar to CW) to a consistent with gender identity pattern at T1 (similar to CM). Overall, the brain patterns stayed the same for the cis people at T0 and T1. CONCLUSIONS: These findings document the impact of hormone treatment, and testosterone supplementation specifically, on emotion perception in TM.

Maternal urinary concentrations of bisphenol A during pregnancy are associated with global DNA methylation in cord blood of newborns in the "NELA" birth cohort.

Endocrine disrupting chemicals (EDCs) set a public health risk through disruption of normal physiological processes. The toxicoepigenetic mechanisms of developmental exposure to common EDCs, such as bisphenol A (BPA), are poorly known. The present study aimed to evaluate associations between perinatal maternal urinary concentrations of BPA, bisphenol S (BPS) and bisphenol F (BPF) and LINE-1 (long interspersed nuclear elements) and Alu (short interspersed nuclear elements, SINEs) DNA methylation levels in newborns, as surrogate markers of global DNA methylation. Data come from 318 mother-child pairs of the `Nutrition in Early Life and Asthma´ (NELA) birth cohort. Urinary bisphenol concentration was measured by dispersive liquid-liquid microextraction and ultrahigh performance liquid chromatography with tandem mass spectrometry detection. DNA methylation was quantitatively assessed by bisulphite pyrosequencing on 3 LINEs and 5 SINEs. Unadjusted linear regression analyses showed that higher concentration of maternal urinary BPA in 24th week's pregnancy was associated with an increase in LINE-1 methylation in all newborns (p = 0.01) and, particularly, in male newborns (p = 0.03). These associations remained in full adjusted models [beta = 0.09 (95 % CI = 0.03; 0.14) for all newborns; and beta = 0.10 (95 % CI = 0.03; 0.17) for males], including a non-linear association for female newborns as well (p-trend = 0.003). No associations were found between maternal concentrations of bisphenol and Alu sequences. Our results suggest that exposure to environmental levels of BPA may be associated with a modest increase in LINE-1 methylation -as a relevant marker of epigenomic stability- during human fetal development. However, any effects on global DNA methylation are likely to be small, and of uncertain biological significance.

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.

Minority Stress and the Effects on Emotion Processing in Transgender Men and Cisgender People: A Study Combining fMRI and 1H-MRS.

BACKGROUND: Minority stress via discrimination, stigmatization, and exposure to violence can lead to development of mood and anxiety disorders and underlying neurobiochemical changes. To date, the neural and neurochemical correlates of emotion processing in transgender people (and their interaction) are unknown. METHODS: This study combined functional magnetic resonance imaging and magnetic resonance spectroscopy to uncover the effects of anxiety and perceived stress on the neural and neurochemical substrates, specifically choline, on emotion processing in transgender men. Thirty transgender men (TM), 30 cisgender men, and 35 cisgender women passively viewed angry, neutral, happy, and surprised faces in the functional magnetic resonance imaging scanner, underwent a magnetic resonance spectroscopy scan, and filled out mood- and anxiety-related questionnaires. RESULTS: As predicted, choline levels modulated the relationship between anxiety and stress symptoms and the neural response to angry and surprised (but not happy faces) in the amygdala. This was the case only for TM but not cisgender comparisons. More generally, neural responses in the left amygdala, left middle frontal gyrus, and medial frontal gyrus to emotional faces in TM resembled that of cisgender women. CONCLUSIONS: These results provide first evidence, to our knowledge, of a critical interaction between levels of analysis and that choline may influence neural processing of emotion in individuals prone to minority stress.

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.

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.

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.

Characterization of the 1H-MRS Metabolite Spectra in Transgender Men with Gender Dysphoria and Cisgender People.

Much research has been conducted on sexual differences of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual differences at the metabolite level using magnetic resonance spectroscopy (1H-MRS) have not been explored in transgender people. In this study, 28 cisgender men (CM) and 34 cisgender women (CW) and 29 transgender men with GD (TMGD) underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, levels of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate and glutamine (Glx), and myo-inositol + glycine (mI + Gly) were assessed in two brain regions, the amygdala-anterior hippocampus and the lateral parietal cortex. The results indicated a sex-assigned at birth pattern for Cho/Cr in the amygdala of TMGD. In the parietal cortex, a sex-assigned at birth and an intermediate pattern were found. Though assessed post-hoc, exploration of the age of onset of GD in TMGD demonstrated within-group differences in absolute NAA and relative Cho/Cr levels, suggestive for a possible developmental trend. While brain metabolite levels in TMGD resembled those of CW, some interesting findings, such as modulation of metabolite concentrations by age of onset of GD, warrant future inquiry.

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.

The Effects of Testosterone on the Brain of Transgender Men.

Transgender men (TM) experience an incongruence between the female sex assigned when they were born and their self-perceived male identity. Some TM seek for a gender affirming hormone treatment (GAHT) to induce a somatic transition from female to male through continuous administration of testosterone. GAHT seems to be relatively safe. However, testosterone produces structural changes in the brain as detected by quantitative magnetic resonance imaging. Mainly, it induces an increase in cortical volume and thickness and subcortical structural volume probably due to the anabolic effects. Animal models, specifically developed to test the anabolic hypothesis, suggest that testosterone and estradiol, its aromatized metabolite, participate in the control of astrocyte water trafficking, thereby controlling brain volume.

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.