Analysis of single nucleotide polymorphisms of the metabotropic glutamate receptors in a transgender population.

Introduction: Gender incongruence (GI) is characterized by a marked incongruence between an individual's experienced/expressed gender and the assigned sex at birth. It includes strong displeasure about his or her sexual anatomy and secondary sex characteristics. In some people, this condition produces a strong distress with anxiety and depression named gender dysphoria (GD). This condition appears to be associated with genetic, epigenetics, hormonal as well as social factors. Given that L-glutamate is the major excitatory neurotransmitter in the central nervous system, also associated with male sexual behavior as well as depression, we aimed to determine whether metabotropic glutamate receptors are involved in GD. Methods: We analyzed 74 single nucleotide polymorphisms located at the metabotropic glutamate receptors (mGluR1, mGluR3, mGluR4, mGluR5, mGluR7 and mGluR8) in 94 transgender versus 94 cisgender people. The allele and genotype frequencies were analyzed by c2 test contrasting male and female cisgender and transgender populations. The strength of the associations was measured by binary logistic regression, estimating the odds ratio (OR) for each genotype. Measurement of linkage disequilibrium, and subsequent measurement of haplotype frequencies were also performed considering three levels of significance: P ≤ 0.05, P ≤ 0.005 and P ≤ 0.0005. Furthermore, false positives were controlled with the Bonferroni correction (P ≤ 0.05/74 = 0.00067). Results: After analysis of allele and genotypic frequencies, we found twenty-five polymorphisms with significant differences at level P ≤ 0.05, five at P ≤ 0.005 and two at P ≤ 0.0005. Furthermore, the only two polymorphisms (rs9838094 and rs1818033) that passed the Bonferroni correction were both related to the metabotropic glutamate receptor 7 (mGluR7) and showed significant differences for multiple patterns of inheritance. Moreover, the haplotype T/G [OR=0.34 (0.19-0.62); P<0.0004] had a lower representation in the transgender population than in the cisgender population, with no evidence of sex cross-interaction. Conclusion: We provide genetic evidence that the mGluR7, and therefore glutamatergic neurotransmission, may be involved in GI and GD.

Gender Dysphoria and DNA.

Gender dysphoria (GD) describes individuals for whom the native sex and expressed gender are not coincident and most of them self-identify as transgender women or men. It has been shown that genetic factors play an important role in GD and the presence of specific genetic variants in candidate genes could be correlated. On the other hand, twins studies have estimated its heritability. In this review, we collect and report the available data obtained by different molecular genetic studies.

Sex Chromosome Rearrangement Associated With Hormonal Abnormalities and Gender Dysphoria.

Although disorders arising from sex chromosome and sex steroid abnormalities are well characterized from the perspectives of endocrinology, dysmorphology, and reproductive health, relatively little is known about neuropsychiatric development, gender identity, incongruence, and dysphoria in the populations with these disorders. In this report, we describe the case of a 21-year-old gender nonbinary individual identified as male at birth who presented to an academic psychiatry consultation clinic because of life-long gender dysphoria. The patient was found to have a complex sex chromosomal rearrangement and associated hormonal abnormalities that may, at least in part, explain the patient's history. In addition to describing a novel genetic change, this case and the accompanying review of the existing literature highlight the need for an increased focus on the psychiatric perspective, and sex and gender issues in particular, among all patients with sex chromosome abnormalities and inborn errors of steroid metabolism.

Concordance for Gender Dysphoria in Genetic Female Monozygotic (Identical) Triplets.

The biopsychosocial etiology of gender dysphoria is poorly understood, but current thought suggests a complex interaction of genetic, hormonal, environmental, and differences in brain development and physiology. Twin studies have implicated a genetic role in the formation of gender identity. Congruence for gender dysphoria is more common among monozygotic twins compared to dizygotic twins. We present a case of monozygotic (identical) triplets who have each transitioned from female to male under the care of a university transgender health service. Each triplet experienced gender dysphoria from childhood and has undergone transitional endocrine care and various aspects of gender-affirming surgery. Although a pure genetic or biological component cannot be attributed as a cause of their gender dysphoria with absolute certainty since the triplets were raised together, this unusual case of gender dysphoria among a set of monozygotic triplets adds support for a heritable role in gender identity formation.

One hundred twelve cases of 46, XY DSD patients after initial gender assignment: a short-term survey of gender role and gender dysphoria.

BACKGROUND: 46, XY disorders of sex development (46, XY DSD) are congenital disorders with 46, XY chromosomal karyotype but inconsistent gonadal/phenotypic sex. One of the biggest concerns for parents and clinicians is the gender assignment. However, there is no standard uniform of care nor consensus at present. We sought to evaluate the current treatment's rationality and provide a reference basis for the gender reassignment in 46, XY DSD patients with a specific diagnosis. METHODS: We conducted a cross-sectional survey of gender role with the Pre-school Activities Inventory (PSAI), the Children's Sex Role Inventory (CSRI) in 46, XY DSD patients and set up control groups comparison. Psychiatrist assessed gender dysphoria in patients ≥ 8-year-old with the criteria of diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). RESULTS: A total of 112 responders of 136 patients participated in this study (82.4%, aged 2-17.8 years, median age: 4-year-old). The follow-up period was from 6 months to 10 years (median: 2 years). Twenty-five females were reassigned to the male gender after a specific diagnosis (16/25 (64%) in 5 alfa-reductase-2 deficiency (5α-RD2), 5/25 (20%) in partial androgen insensitivity syndrome (PAIS), 4/25 (16%) in NR5A1gene mutation). Male gender assignment increased from 55.3 (n = 62) to 77.7% (n = 87). The median PSAI score was similar to the control males in 5α-RD2, PAIS, and NR5A1 gene mutation groups (p > 0.05); while identical to the control females in complete androgen insensitivity syndrome (CAIS) and CYP17A1 gene mutation groups (p > 0.05). PSAI score of children raised as male was higher than those of CAIS and CYP17A1 groups raised as female (p < 0.05). CSRI scale showed no statistical differences in the consistency of gender roles and reassigned gender between 46, XY DSD patients and control groups (p > 0.05). None of the patients over 8-year-old (n = 44) had gender dysphoria. CONCLUSION: The reassigned gender in 46, XY DSD patients is consistent with their gender role during early childhood. None of them had gender dysphoria. The molecular diagnosis, gonadal function, and the gender reassignment are congruent within our Chinese cohort. Long-term follow-up and more evaluation are still required.

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.

5α-Reductase-2 deficiency: is gender assignment recommended in infancy? Two case-reports and review of the literature.

PURPOSE: Gender assignment represents one of the most controversial aspects of the clinical management of individuals with Differences of Sex Development, including 5α-Reductase-2 deficiency (SRD5A2). Given the predominant female appearance of external genitalia in individuals with SRD5A2 deficiency, most of them were assigned to the female sex at birth. However, in the last years the high rate of gender role shift from female to male led to recommend a male gender assignment. METHODS: We here describe two cases of subjects with SRD5A2 deficiency assigned as females at birth, reporting their clinical histories and psychometric evaluations (Body Uneasiness Test, Utrecht Gender Dysphoria Scale, Bem Sex-Role Inventory, Female Sexual Distress Scale Revised, visual analogue scale for gender identity and sexual orientation) performed at the time of referral at the Florence Gender Clinic. RESULTS: Both patients underwent early surgical interventions without being included in the decision-making process. They had to conform to a binary feminine gender role because of social/familiar pressure, with a significant impact on their psychological well-being. Psychometric evaluations identified clinically significant body uneasiness and gender incongruence in both subjects. No sexually related distress and undifferentiated gender role resulted in the first subject and sexually related distress and androgynous gender role resulted in the second subject. CONCLUSIONS: The reported cases suggest the possibility to consider a new approach for gender assignment in these individuals, involving them directly in the decision-making process and allowing them to explore their gender identity, also with the help of GnRH analogues to delay pubertal modifications.

[Chromosome Analysis in the Assessment for Gender Affirmation Process: A Retrospective Study]. / Cinsiyet Uyum Süreciyle Ilgili Degerlendirmede Kromozom Analizi: Geriye Dönük Arastirma.

OBJECTIVE: Gender dysphoria refers to the experienced discomfort related to the incongruence between gender identity and the sex assigned at birth. Current treatment approach for this clinical condition is gender affirmation procedures. International guidelines about gender affirmation do not recommend routine genetic evaluation. In Turkey, provision of health insurance for medical expenses incurred by these procedures requires genetic consultation which frequently involves chromosome analysis (karyotyping). However, the contribution of routine chromosome analysis to the assessment and management of gender dysphoria is not established. This study aims to assess the results of chromosome analysis and its effect on the management of gender dysphoria. METHOD: The completed chromosome analysis results and observational records of 217 individuals among a total of 281 evaluated for gender affirmation in the psychiatry polyclinic were investigated retrospectively. RESULTS: The chromosome analysis results of 213 (98.2 %) of the 217 individuals investigated were congruent with the sex assigned at birth. Variations were found in the karyotypes of 4 individuals with female sex assigned at birth, only 1 of whom had been diagnosed with a disorder of sex development. In the other cases, however, chromosome analysis did not affect the diagnosis or the clinical intervention. CONCLUSION: Finding that routine chromosome analysis during the assessment for gender affirmation process rarely affected the clinical diagnosis and the treatment was consistent with the reports of previous studies and supported the recommendation that chromosome analysis should be carried out only in cases where history, physical examination and the required imaging investigations suggested a disorder sex development.

Gender dysphoria and XX congenital adrenal hyperplasia: how frequent is it? Is male-sex rearing a good idea?

INTRODUCTION: The frequency of gender dysphoria (GD) among 46,XX congenital adrenal hyperplasia (CAH) patients is unknown. These data are needed to put into perspective the debate about the timing of reconstructive surgery and possible male-raising of the most severely virilized children. OBJECTIVE: To analyze the frequency of female to male GD between 46,XX individuals raised as females; to identify subgroups with higher chances of showing GD; to describe the results of male-raising among 46,XX CAH patients. MATERIALS AND METHODS: Analytic/descriptive literature review (January 1988 to April 2018). RESULTS: Female-raised patients frequently report the desire to be male, adopt male-typical behavior and are frequently homosexual/bisexual as adults, but this does not correspond to GD. Declared GD among 46,XX CAH patients attained 9% of the reported cohorts, generally in late adolescence/adulthood. We could not prove a relationship between inadequate treatment, null-genotype, late diagnoses, a higher degree of virilization, type of CAH or higher levels of androgens and female to male GD, but this may be due to statistical limitations. Male gender raised patients (MGR) were 10.1% of CAH cohorts included in this review, mostly from underdeveloped countries, with a high proportion of late diagnoses (76.3%) and familial choices. GD was more common in this group than among female-raised patients. Opting for male gender relates to a short final height, the need for multiple surgeries, surgical castration before puberty and infertility. CONCLUSION: Both male to female and female to male GD may present in 46,XX CAH patients in a contemporaneous cohort. The proportion of GD is higher among patients raised as males. DSD patients sexual maladjustments are complex and not comparable to the transgender population. Many 46,XX CAH patients with GD define themselves as gender-fluid and do not seek for legal/formal transition. Male-raising Prader 4/5 46,XX CAH patients imply infertility and multiple surgeries. There is no proof that any subgroup of CAH is more prone to GD, despite null genotypes, salt wasting phenotypes and Prader 4/5 cases being related to male-typical behavior and female homosexuality. TYPE OF STUDY: Descriptive/analytic non-systematic REVIEW. LEVEL OF EVIDENCE: 3.

Genetic Link Between Gender Dysphoria and Sex Hormone Signaling.

Context: There is a likely genetic component to gender dysphoria, but association study data have been equivocal. Objective: We explored the specific hypothesis that gender dysphoria in transgender women is associated with variants in sex hormone-signaling genes responsible for undermasculinization and/or feminization. Design: Subject-control analysis included 380 transgender women and 344 control male subjects. Associations and interactions were investigated between functional variants in 12 sex hormone-signaling genes and gender dysphoria in transgender women. Setting: Patients were recruited from the Monash Gender Clinic, Monash Health, Melbourne, Australia, and the University of California, Los Angeles. Patients: Caucasian (non-Latino) transgender women were recruited who received a diagnosis of transsexualism [Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV) or gender dysphoria (DSM-V)] pre- or postoperatively. Most were receiving hormone treatment at the time of recruitment. Main Outcome Measured: Genomic DNA was genotyped for repeat length polymorphisms or single nucleotide polymorphisms. Results: A significant association was identified between gender dysphoria and ERα, SRD5A2, and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele combinations were also overrepresented in transgender women, most involving AR (namely, AR-ERß, AR-PGR, AR-COMT, CYP17-SRD5A2). Overrepresented alleles and genotypes are proposed to undermasculinize/feminize on the basis of their reported effects in other disease contexts. Conclusion: Gender dysphoria may have an oligogenic component, with several genes involved in sex hormone-signaling contributing.

Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction.

BACKGROUND: Polymorphisms in sex steroid receptors have been associated with transsexualism. However, published replication studies have yielded inconsistent findings, possibly because of a limited sample size and/or the heterogeneity of the transsexual population with respect to the onset of dysphoria and sexual orientation. We assessed the role of androgen receptor (AR), estrogen receptors alpha (ERα) and beta (ERß), and aromatase (CYP19A1) in two large and homogeneous transsexual male-to-female (MtF) and female-to-male (FtM) populations. METHODS: The association of each polymorphism with transsexualism was studied with a twofold subject-control analysis: in a homogeneous population of 549 early onset androphilic MtF transsexuals versus 728 male controls, and 425 gynephilic FtMs versus 599 female controls. Associations and interactions were investigated using binary logistic regression. RESULTS: Our data show that specific allele and genotype combinations of ERß, ERα and AR are implicated in the genetic basis of transsexualism, and that MtF gender development requires AR, which must be accompanied by ERß. An inverse allele interaction between ERß and AR is characteristic of the MtF population: when either of these polymorphisms is short, the other is long. ERß and ERα are also associated with transsexualism in the FtM population although there was no interaction between the polymorphisms. Our data show that ERß plays a key role in the typical brain differentiation of humans. CONCLUSION: ERß plays a key role in human gender differentiation in males and females.

Analyses of karyotype by G-banding and high-resolution microarrays in a gender dysphoria population.

Gender Dysphoria is characterized by a marked incongruence between the cerebral sex and biological sex. To investigate the possible influence of karyotype on the etiology of Gender Dysphoria we carried out the cytogenetic analysis of karyotypes in 444 male-to-females (MtFs) and 273 female-to-males (FtMs) that attended the Gender Identity Units of Barcelona and Málaga (Spain) between 2000 and 2016. The karyotypes from 23 subjects (18 MtFs and 5 FtMs) were also analysed by Affymetrix CytoScan™ high-density (HD) arrays. Our data showed a higher incidence of cytogenetic alterations in Gender Dysphoria (2.65%) than in the general population (0.53%) (p < 0.0001). When G-banding was performed, 11 MtFs (2.48%) and 8 FtMs (2.93%) showed a cytogenetic alteration. Specifically, Klinefelter syndrome frequency was significantly higher (1.13%) (p < 0.0001), however Turner syndrome was not represented in our sample (p < 0.61). At molecular level, HD microarray analysis revealed a 17q21.31 microduplication which encompasses the gene KANSL1 (MIM612452) in 5 out of 18 MtFs and 2 out of 5 FtMs that corresponds to a copy-number variation region in chromosome 17q21.31. In conclusion, we confirm a significantly high frequency of aneuploidy, specifically Klinefelter syndrome and we identified in 7 out of 23 GD individuals the same microduplication of 572 Kb which encompasses the KANSL1 gene.

The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the Table.

The American Psychological Association defines gender identity as, "A person's deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person's sex assigned at birth or to a person's primary or secondary sex characteristics" (American Psychological Association, Am Psychol 70(9):832-864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.

¿La identidad sexual es una opción? Un estudio sobre la basegenética de la Transexualidad / Is sexual identity optional? A study of the genetics of transsexuality

La Transexualidad según el ICD-10 (Clasificación Internacional de Enfermedades, décima edición), o Disforia de Género en adolescentes y adultos en el DSM-5 (Manual Diagnóstico y Estadístico de Desórdenes Mentales, quinta edición), se caracteriza por una marcada incongruencia entre género y sexo biológico. La etiología de la Disforia de Género (DG) o Transexualidad es compleja. Algunas hipótesis señalan una discrepancia entre sexo cerebral y sexo biológico. Otras evidencias sugieren una vulnerabilidad genética. Henningsson y col, (2004) encontraron diferencias estadísticamente significativas cuando examinaron el receptor de estrógenos Beta (ERß) y el receptor de andrógenos (AR) en una población MtF (del inglés male-to-female). Los autores sugieren que en la población MtF son más frecuentes las formas largas de los genes ERBeta y AR. Hare y col, (2009) también encontraron una asociación significativa entre el tamaño del gen AR y la DG. Nuestro grupo replicó los trabajos de Henningsson y col, (2004) y Hare y col, (2009) en una de las poblaciones con DG más grande analizada hasta el momento, confirmando la implicación de los receptores de estrógenos formas alfa y Beta) y el receptor de andrógenos, en la base genética de la DG. Nuestros datos apoyan la existencia de una vulnerabilidad genética de la DG tanto en la población MtF como en la FtM. Corroboran la implicación de los receptores de estrógenos alfa y beta y el receptor de andrógenos en la masculinización del cerebro en humanos. Confirman así mismo que la identidad sexual no es una opción, sino que viene determinada genéticamente, aunque posee un componente hormonal muy importante. Su substrato por tanto, no es ideológico, sino cerebral

Transsexualism in the ICD-10 (International Classification of Diseases, Tenth Revision), Gender Dysphoria in adolescents and adults in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), is characterized by a marked incongruence between one’s experienced gender and biological sex. The etiology is complex, but some hypotheses suggest that Gender Dysphoria (GD) arises from discrepant cerebral and biological sexual differentiation. Increasingevidence supports the idea of genetic vulnerability. Henningsson et al, (2004) found significant differences when they examined estrogen receptor Beta (ER Beta) in a male-to-female (MtF) population. They suggested that a long ER Beta polymorphism is more common in MtFs. Hare et al, (2009) also examined an MtF population and found a significant association between the androgen receptor (AR) and GD. Our group analyzed the same polymorphisms and found an association between ER alfa, ER Beta and AR in GD. Our results suggest a genetic basis of GD in MtF and FtM populations. Our data corroborate the implication of the two estrogen receptors, ERalfa and Beta, and the androgen receptor in the genetic basis of GD, and advise the importance of estrogens and androgens in cerebral masculinization. Our data also confirm that sexual identity is not optional, but is determined prenatally by the genes, although it has a very importanthormonal component. Therefore, its substrate is cerebral, not ideological

Genomic Characteristics of Gender Dysphoria Patients and Identification of Rare Mutations in RYR3 Gene.

Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.

Effects of sex steroids on the pattern of methylation and expression of the promoter region of estrogen and androgen receptors in people with gender dysphoria under cross-sex hormone treatment.

Cross-sex hormone therapy (CHT) is critical for phenotypical and physiological transition in adults with gender dysphoria (GD). However, the impact of the CHT onto the molecular level/epigenetic regulation has not been comprehensively addressed. We postulate that CHT in GD could drive changes at the androgen receptor (AR), estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), affecting their DNA methylation pattern and mRNA expression that may influence in the phenotypical changes associated to CHT. We carried out a prospective observational study on individuals with a diagnosis of GD. 18 subjects (no previous CHT): 12 female to male (FtoM) and 6 male to female (MtoF). An Epityper Mass array TM method was used to study the DNA methylation and Real-time PCR quantitative reverse transcription PCR (qRT-PCR) was used to quantify the gene expression. The analysis of AR, ESR1 and ESR2 receptor was performed at baseline, 6 and 12 months after CHT. No differences in DNA methylation of ESR were found in MtoF, while DNA methylation was increased in FtoM at 6 and 12 months of CHT. The AR showed a significant increase of methylation in MtoF group after 12 months of estrogenic treatment. Regarding the expression analysis, AR expression was significantly decreased in FtoM upon CHT treatment. AR, ESR1 and ESR2 methylation were correlated with anthropometric, metabolic and hormonal parameters in FtoM and MtoF. Our results support that CHT is associated to epigenetic changes that might affect the response to treatment with sex steroids.

Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria.

INTRODUCTION: Gender dysphoria, a marked incongruence between one's experienced gender and biological sex, is commonly believed to arise from discrepant cerebral and genital sexual differentiation. With the discovery that estrogen receptor ß is associated with female-to-male (FtM) but not with male-to-female (MtF) gender dysphoria, and given estrogen receptor α involvement in central nervous system masculinization, it was hypothesized that estrogen receptor α, encoded by the ESR1 gene, also might be implicated. AIM: To investigate whether ESR1 polymorphisms (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults. METHODS: Molecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex- and ethnically-matched controls. MAIN OUTCOME MEASURES: Genotype and haplotype analyses of the (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms. RESULTS: Allele and genotype frequencies for the polymorphism XbaI were statistically significant only in FtM vs control XX subjects (P = .021 and P = .020). In XX individuals, the A/G genotype was associated with a low risk of gender dysphoria (odds ratio [OR] = 0.34; 95% CI = 0.16-0.74; P = .011); in XY individuals, the A/A genotype implied a low risk of gender dysphoria (OR = 0.39; 95% CI = 0.17-0.89; P = .008). Binary logistic regression showed partial effects for all three polymorphisms in FtM but not in MtF subjects. The three polymorphisms were in linkage disequilibrium: a small number of TA repeats was linked to the presence of PvuII and XbaI restriction sites (haplotype S-T-A), and a large number of TA repeats was linked to the absence of these restriction sites (haplotype L-C-G). In XX individuals, the presence of haplotype L-C-G carried a low risk of gender dysphoria (OR = 0.66; 95% CI = 0.44-0.99; P = .046), whereas the presence of haplotype L-C-A carried a high susceptibility to gender dysphoria (OR = 3.96; 95% CI = 1.04-15.02; P = .044). Global haplotype was associated with FtM gender dysphoria (P = .017) but not with MtF gender dysphoria. CONCLUSIONS: XbaI-rs9340799 is involved in FtM gender dysphoria in adults. Our findings suggest different genetic programs for gender dysphoria in men and women. Cortés-Cortés J, Fernández R, Teijeiro N, et al. Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria. J Sex Med 2017;14:464-472.

Genetic and Environmental Influences on Traits of Gender Identity Disorder: A Study of Japanese Twins Across Developmental Stages.

The present study examined: (1) gender and age differences of mean gender identity disorder (GID) trait scores in Japanese twins; (2) the validity of the prenatal hormone transfer theory, which predicts that, in dizygotic (DZ) twin pairs, twins with an opposite-gender co-twin more frequently exhibit GID traits than twins with a same-gender co-twin; and (3) the magnitude of genetic and environmental influences on GID traits as a function of age and gender. Data from 1450 male twin pairs, 1882 female twin pairs, and 1022 DZ male-female pairs ranging from 3 to 26 years of age were analyzed. To quantify individual variances in GID traits, each participant completed four questionnaire items based on criteria for GID from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Our most important findings were: (1) Japanese females exhibited GID traits more frequently than males and Japanese children exhibited GID traits less frequently than adolescents and adults (among females, the prevalence was 1.6 % in children, 10 % in adolescents, and 12 % in adults; among males, the prevalence was 0.5, 2, and 3 %, respectively); (2) the data did not support the prenatal hormone transfer theory for GID traits; and (3) a large part of the variance for GID traits in children was accounted for by familial factors; however, the magnitude was found to be greater in children than in adolescents or adults, particularly among females. This study suggests that although the prevalence is likely to increase, familial effects are likely to decrease as individuals age.

Transexualidad: una alteración cerebral que comienza a conocerse / Transsexualism: a brain disorder that begins to known

La transexualidad describe la condición de una persona cuyo sexo psicológico difiere del biológico. Las personas con trastorno de identidad de género sufren de forma persistente por esta incongruencia y buscan un cambio de la anatomía sexual, mediante tratamiento hormonal y quirúrgico. Esta revisión, desde una perspectiva ética, ofrece una visión de las correlaciones neurobiológicas estructurales y funcionales de la transexualidad y los procesos de cambio cerebrales por la administración de las hormonas del sexo deseado. Varios estudios demuestran un aumento de la conectividad funcional entre regiones de la corteza cerebral, que son huellas de la angustia psicosocial generada por la discordancia entre el sexo psicológico y el biológico. Tal angustia se puede atribuir a una imagen corporal incongruente debida a los cambios en la conectividad funcional de los componentes clave de la red de representación del cuerpo. Parte de los cambios de la conectividad suponen un mecanismo de defensa puesto que disocia la emoción sentida de la imagen corporal. Las personas transexuales presentan signos de feminización o masculinización de estructuras y procesos cerebrales con dimorfismo sexual y que durante la administración hormonal se desplazan parcialmente aún más hacia las correspondientes al sexo deseado. Estos cambios permiten una reducción de la angustia psicosocial. Sin embargo, un modelo de 'reasignación del sexo' no resuelve el problema, puesto que no se trata la alteración cerebral que lo causa. Se trata de una grave cuestión de ética médica. La liberación de los prejuicios para conocer lo que ocurre en el cerebro de los transexuales es una necesidad médica, tanto para definir lo que es y no es un tratamiento terapéutico, como para guiar las acciones legales

Transsexualism describes the condition when a person’s psychological gender differs from his or her biological sex. People with gender identity disorder suffer persistently from this incongruence and they search hormonal and surgical sex reassignment to the desired anatomical sex. This review, from an ethical perspective, intends to give an overview of structural and functional neurobiological correlations of transsexualism and their course under cross-sex hormonal administration. Several studies demonstrate an increased functional connectivity between cortex regions reaffirming psychosocial distress of psychologicalbiological sex incongruity. Such distress can be ascribed to a disharmonic body image due to changes in the functional connectivity of the key components of body representation network. These brain alterations seem to imply a strategic mechanism dissociating bodily emotions from bodily images. For a number of sexually dimorphic brain structures or processes, signs of feminization or masculinization are observable in transsexual individuals, who during hormonal administration seem to partly further adjust to characteristics of the desired sex. These changes allow a reduction of psychosocial distress. However, a model leading to a 'gender affirmation' does not solve the problem, since brain disorders causing it are not corrected. This is a serious medical ethics issue. Prejudices should be left aside. To know what happens in the brain of transsexuals is a medical need, both to define what is and what is not, and so to choose an adequate treatment, and to decide and guide legal actions

Phenotype, genotype and gender identity in a large cohort of patients from India with 5α-reductase 2 deficiency.

Deficiency of the 5α-reductase 2 enzyme impairs the conversion of testosterone to dihydrotestosterone (DHT) and differentiation of external genitalia, seminal vesicles and prostate in males. The present study describes the phenotype, genotype and gender identity in a large cohort of patients with 5αRD2. All patients underwent detailed clinical evaluation, hormonal profile, karyotyping and molecular analysis of the SRD5A2 gene. The molecular analysis of the SRD5A2 gene showed the presence of mutant alleles in 24 patients. We found 6 novel mutations IVS(1-2) T>C, p.A52T, 188-189insTA, 904-905ins A, p.A12T and p.E57X in our patients. All patients had ambiguous genitalia and the degrees of under-virilization ranged from penoscrotal hypospadias and microphallus to clitoromegaly. The position of gonads was variable in patients with same mutation. All the patients with mutations in the SRD5A2 gene had male gender identity. Those reared as female had gender dysphoria and underwent gender reassignment. Though a specific genotype-phenotype correlation could not be established in our patient but confirming the diagnosis of 5αRD2 with assessment of the SRD5A2 gene may help in appropriate gender assignment.