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.

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.

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.

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.

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.

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.

Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile.

Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.

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.

Aesthetic Refinement in the Creation of the Clitoris, Its Preputial Hood, and Labia Minora in Male-to-Female Transsexual Patients.

BACKGROUND: In male-to-female genital sex reassignment surgery, the clitoris, its prepuce, and the labia minora remain among the most difficult structures to construct. We describe the authors' clitoroplasty and vulvoplasty technique. METHODS: All patients who underwent male-to-female sex reassignment surgery at a single center, between June 2012 and June 2016, were prospectively included. The standard pedicled island neurovascular flap of the glans penis was harvested in a letter M fashion with attached preputial skin. The central triangle of the M was used for the neoclitoris formation. Labia minora and the clitoral prepuce were created with both legs of the M and the preputial skin attached to it. Tactile and erogenous sensitivity was evaluated. RESULTS: Ninety-seven patients were included (mean age, 32 years; range, 17-54 years). All clitoroplasties and vulvoplasties were completed in the same surgical stage as the vaginoplasty. There were no cases of deep or total flap necrosis. Eight patients developed partial and superficial skin necrosis of the flap; one presented an abscess in labia majora, and another patient had urethral hematoma; both required drainage. None of the complications left any sequelae. At 6 months' follow-up all patients maintained tactile and erogenous sensitivity. CONCLUSIONS: The proposed technique represents an aesthetic refinement of the previously described pedicled glans penis flap by allowing the creation of a sensate neoclitoris, its preputial hood, and labia minora with excellent outcomes in the same surgical stage as the sex reassignment.

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.

A Review of the Status of Brain Structure Research in Transsexualism.

The present review focuses on the brain structure of male-to-female (MtF) and female-to-male (FtM) homosexual transsexuals before and after cross-sex hormone treatment as shown by in vivo neuroimaging techniques. Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females. These phenotypes have theoretical implications for brain intersexuality, asymmetry, and body perception in transsexuals as well as for Blanchard's hypothesis on sexual orientation in homosexual MtFs. Falling within the aegis of the neurohormonal theory of sex differences, we hypothesize that cortical differences between homosexual MtFs and FtMs and male and female controls are due to differently timed cortical thinning in different regions for each group. Cross-sex hormone studies have reported marked effects of the treatment on MtF and FtM brains. Their results are used to discuss the early postmortem histological studies of the MtF brain.

Sexual quality of life in gender-dysphoric adults before genital sex reassignment surgery.

INTRODUCTION: Although there is literature on sexuality in gender dysphoria, few studies have been done prior to genital sex reassignment surgery (SRS). AIMS: To evaluate the perception of sexual QoL in gender-dysphoric patients before genital SRS and the possible factors associated to this perception. METHODS: The final sample consisted of 67 male-to-female and 36 female-to-male gender-dysphoric adults consecutively attended in a gender unit who had not undergone genital SRS; 39.8% was receiving cross-sex hormonal treatment, and 30.1% had undergone breast augmentation or reduction. Sexual QoL was assessed using the sexual activity facet of the World Health Organization Quality of Life (WHOQOL)-100. Sociodemographic (age, gender, partner relationship) and clinical data (being on hormonal treatment and having undergone any breast surgery) were recorded from the clinical records. Depressive symptoms were assessed using the negative feelings facet of the WHOQOL-100. Personality was assessed using the Revised NEO-Five Factor Inventory. MAIN OUTCOME MEASURES: Sexual QoL, negative feelings, hormonal treatment, partner relationship, personality. RESULTS: The mean score of the sexual facet was 10.01 (standard deviation = 4.09). More than 50% of patients rated their sexual life as "poor/dissatisfied" or "very poor/very dissatisfied," around a quarter rated it as "good/satisfied" or "very good/very satisfied," and the rest had a neutral perception. Three variables were significantly associated with a better sexual QoL: less negative feelings (ß = -0.356; P < 0.001), being on hormonal treatment (ß = 0.216; P = 0.018), and having a partner (ß = 0.206; P = 0.022). Age, sex, having undergone some breast surgery, and personality factors were not associated with their perception. CONCLUSION: This study indicates that before genital SRS, about half of gender-dysphoric subjects perceived their sexual life as "poor/dissatisfied" or "very poor/very dissatisfied." Moreover, receiving hormonal treatment, low negative feelings, and having a partner are related to a better subjective perception of sexual QoL.

The CYP17†MspA1 Polymorphism and the Gender Dysphoria.

INTRODUCTION: The A2 allele of the CYP17 MspA1 polymorphism has been linked to higher levels of serum testosterone, progesterone, and estradiol. AIM: To determine whether the CYP17 MspA1 polymorphism is associated with transsexualism. METHODS: We analyzed 151 male-to-female (MtF), 142 female-to-male (FtM), 167 control male, and 168 control female individuals. Fragments that included the mutation were amplified by PCR and digested with MspA1. Our data were compared with the allele/genotype frequencies provided by the 1000 Genomes Data Base, and contrasted with a MEDLINE search of the CYP17 MspA1 polymorphism in the literature. MAIN OUTCOME MEASURES: We investigated the association between transsexualism and the CYP17 MspA1 polymorphism. RESULTS: A2 frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887). This observation concurred with the 1000 Genomes Data Base and the MEDLINE search. CONCLUSION: Our data confirm a sex-dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM > MtF, suggestive of a hypothetical A2 involvement in transsexualism since the allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex.

Effects of cross-sex hormone treatment on cortical thickness in transsexual individuals.

INTRODUCTION: Untreated transsexuals have a brain cortical phenotype. Cross-sex hormone treatments are used to masculinize or feminize the bodies of female-to-male (FtMs) or male-to-female (MtFs) transsexuals, respectively. AIM: A longitudinal design was conducted to investigate the effects of treatments on brain cortical thickness (CTh) of FtMs and MtFs. METHODS: This study investigated 15 female-to-male (FtMs) and 14 male-to-female (MtFs) transsexuals prior and during at least six months of cross-sex hormone therapy treatment. Brain MRI imaging was performed in a 3-Tesla TIM-TRIO Siemens scanner. T1-weighted images were analyzed with FreeSurfer software to obtain CTh as well as subcortical volumetric values. MAIN OUTCOME MEASURES: Changes in brain CTh thickness and volumetry associated to changes in hormonal levels due to cross-sex hormone therapy. RESULTS: After testosterone treatment, FtMs showed increases of CTh bilaterally in the postcentral gyrus and unilaterally in the inferior parietal, lingual, pericalcarine, and supramarginal areas of the left hemisphere and the rostral middle frontal and the cuneus region of the right hemisphere. There was a significant positive correlation between the serum testosterone and free testosterone index changes and CTh changes in parieto-temporo-occipital regions. In contrast, MtFs, after estrogens and antiandrogens treatment, showed a general decrease in CTh and subcortical volumetric measures and an increase in the volume of the ventricles. CONCLUSIONS: Testosterone therapy increases CTh in FtMs. Thickening in cortical regions is associated to changes in testosterone levels. Estrogens and antiandrogens therapy in MtFs is associated to a decrease in the CTh that consequently induces an enlargement of the ventricular system.

The (CA)n polymorphism of ERß gene is associated with FtM transsexualism.

INTRODUCTION: Transsexualism is a gender identity disorder with a multifactorial etiology. Neurodevelopmental processes and genetic factors seem to be implicated. AIM: The aim of this study was to investigate the possible influence of the sex hormone-related genes ERß (estrogen receptor ß), AR (androgen receptor), and CYP19A1 (aromatase) in the etiology of female-to-male (FtM) transsexualism. METHODS: In 273 FtMs and 371 control females, we carried out a molecular analysis of three variable regions: the CA repeats in intron 5 of ERß; the CAG repeats in exon 1 of AR, and the TTTA repeats in intron 4 of CYP19A1. MAIN OUTCOME MEASURES: We investigated the possible influence of genotype on transsexualism by performing a molecular analysis of the variable regions of genes ERß, AR, and CYP19A1 in 644 individuals (FtMs and control females). RESULTS: FtMs differed significantly from control group with respect to the median repeat length polymorphism ERß (P = 0.002) but not with respect to the length of the other two studied polymorphisms. The repeat numbers in ERß were significantly higher in FtMs than in control group, and the likelihood of developing transsexualism was higher (odds ratio: 2.001 [1.15-3.46]) in the subjects with the genotype homozygous for long alleles. CONCLUSIONS: There is an association between the ERß gene and FtM transsexualism. Our data support the finding that ERß function is directly proportional to the size of the analyzed polymorphism, so a greater number of repeats implies greater transcription activation, possibly by increasing the function of the complex hormone ERß receptor and thereby encouraging less feminization or a defeminization of the female brain and behavior.

Association study of ERß, AR, and CYP19A1 genes and MtF transsexualism.

INTRODUCTION: The etiology of male-to-female (MtF) transsexualism is unknown. Both genetic and neurological factors may play an important role. AIM: To investigate the possible influence of the genetic factor on the etiology of MtF transsexualism. METHODS: We carried out a cytogenetic and molecular analysis in 442 MtFs and 473 healthy, age- and geographical origin-matched XY control males. The karyotype was investigated by G-banding and by high-density array in the transsexual group. The molecular analysis involved three tandem variable regions of genes estrogen receptor ß (ERß) (CA tandem repeats in intron 5), androgen receptor (AR) (CAG tandem repeats in exon 1), and CYP19A1 (TTTA tandem repeats in intron 4). The allele and genotype frequencies, after division into short and long alleles, were obtained. MAIN OUTCOME MEASURES: We investigated the association between genotype and transsexualism by performing a molecular analysis of three variable regions of genes ERß, AR, and CYP19A1 in 915 individuals (442 MtFs and 473 control males). RESULTS: Most MtFs showed an unremarkable 46,XY karyotype (97.96%). No specific chromosome aberration was associated with MtF transsexualism, and prevalence of aneuploidy (2.04%) was slightly higher than in the general population. Molecular analyses showed no significant difference in allelic or genotypic distribution of the genes examined between MtFs and controls. Moreover, molecular findings presented no evidence of an association between the sex hormone-related genes (ERß, AR, and CYP19A1) and MtF transsexualism. CONCLUSIONS: The study suggests that the analysis of karyotype provides limited information in these subjects. Variable regions analyzed from ERß, AR, and CYP19A1 are not associated with MtF transsexualism. Nevertheless, this does not exclude other polymorphic regions not analyzed.

Cortical thickness in untreated transsexuals.

Sex differences in cortical thickness (CTh) have been extensively investigated but as yet there are no reports on CTh in transsexuals. Our aim was to determine whether the CTh pattern in transsexuals before hormonal treatment follows their biological sex or their gender identity. We performed brain magnetic resonance imaging on 94 subjects: 24 untreated female-to-male transsexuals (FtMs), 18 untreated male-to-female transsexuals (MtFs), and 29 male and 23 female controls in a 3-T TIM-TRIO Siemens scanner. T1-weighted images were analyzed to obtain CTh and volumetric subcortical measurements with FreeSurfer software. CTh maps showed control females have thicker cortex than control males in the frontal and parietal regions. In contrast, males have greater right putamen volume. FtMs had a similar CTh to control females and greater CTh than males in the parietal and temporal cortices. FtMs had larger right putamen than females but did not differ from males. MtFs did not differ in CTh from female controls but had greater CTh than control males in the orbitofrontal, insular, and medial occipital regions. In conclusion, FtMs showed evidence of subcortical gray matter masculinization, while MtFs showed evidence of CTh feminization. In both types of transsexuals, the differences with respect to their biological sex are located in the right hemisphere.

Determinants of quality of life in Spanish transsexuals attending a gender unit before genital sex reassignment surgery.

PURPOSE: To evaluate the self-reported perceived quality of life (QoL) in transsexuals attending a Spanish gender identity unit before genital sex reassignment surgery, and to identify possible determinants that likely contribute to their QoL. METHODS: A sample of 119 male-to-female (MF) and 74 female-to-male (FM) transsexuals were included in the study. The WHOQOL-BREF scale was used to evaluate self-reported QoL. Possible determinants included age, sex, education, employment, partnership status, undergoing cross-sex hormonal therapy, receiving at least one non-genital sex reassignment surgery, and family support (assessed with the family APGAR questionnaire). RESULTS: Mean scores of all QoL domains ranged from 55.44 to 63.51. Linear regression analyses revealed that undergoing cross-sex hormonal treatment, having family support, and having an occupation were associated with a better QoL for all transsexuals. FM transsexuals have higher social domain QoL scores than MF transsexuals. The model accounts for 20.6 % of the variance in the physical, 32.5 % in the psychological, 21.9 % in the social, and 20.1 % in the environment domains, and 22.9 % in the global QoL factor. CONCLUSIONS: Cross-sex hormonal treatment, family support, and working or studying are linked to a better self-reported QoL in transsexuals. Healthcare providers should consider these factors when planning interventions to promote the health-related QoL of transsexuals.