Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452.

OBJECTIVE: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. METHODS: Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. RESULTS: Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). CONCLUSION: This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.

17α-ethynylestradiol prevents the natural male-to-female sex change in gilthead seabream (Sparus aurata L.).

Exposure to 17α-ethynylestradiol (EE2, 5 µg/g food) impairs some reproductive events in the protandrous gilthead seabream and a short recovery period does not allow full recovery. In this study, spermiating seabream males in the second reproductive cycle (RC) were fed a diet containing 5 or 2.5 µg EE2/g food for 28 days and then a commercial diet without EE2 for the remaining RC. Individuals were sampled at the end of the EE2 treatment and then at the end of the RC and at the beginning of the third RC, 146 and 333 days after the cessation of treatment, respectively. Increased hepatic transcript levels of the gene coding for vitellogenin (vtg) and plasma levels of Vtg indicated both concentrations of EE2 caused endocrine disruption. Modifications in the histological organization of the testis, germ cell proliferation, plasma levels of the sex steroids and pituitary expression levels of the genes coding for the gonadotropin ß-subunits, fshß and lhß were detected. The plasma levels of Vtg and most of the reproductive parameters were restored 146 days after treatments. However, although 50% of the control fish underwent sex reversal as expected at the third RC, male-to female sex change was prevented by both EE2 concentrations.

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.

Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function.

We have searched the literature for information on the risk of breast cancer (BC) in relation to gender, breast development, and gonadal function in the following 8 populations: 1) females with the Turner syndrome (45, XO); 2) females and males with congenital hypogonadotropic hypogonadism and the Kallmann syndrome; 3) pure gonadal dysgenesis (PGD) in genotypic and phenotypic females and genotypic males (Swyer syndrome); 4) males with the Klinefelter syndrome (47, XXY); 5) male-to-female transgender individuals; 6) female-to-male transgender individuals; 7) genotypic males, but phenotypic females with the complete androgen insensitivity syndrome, and 8) females with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (müllerian agenesis). Based on this search, we have drawn 3 major conclusions. First, the presence of a Y chromosome protects against the development of BC, even when female-size breasts and female-level estrogens are present. Second, without menstrual cycles, BC hardly occurs with an incidence comparable to males. There is a strong correlation between the lifetime number of menstrual cycles and the risk of BC. In our populations the BC risk in genetic females not exposed to progesterone (P4) is very low and comparable to males. Third, BC has been reported only once in genetic females with MRKH syndrome who have normal breasts and ovulating ovaries with normal levels of estrogens and P4. We hypothesize that the oncogenic glycoprotein WNT family member 4 is the link between the genetic cause of MRKH and the absence of BC women with MRKH syndrome.

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.

¿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

[Is Sexual Identity Optional? A Study of The Genetics of Transsexuality]. / ¿La Identidad Sexual Es una Opción? Un Estudio Sobre la Base Genética de la Transexualidad.

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. Increasing evidence supports the idea of genetic vulnerability. Henningsson et al, (2004) found significant differences when they examined estrogen receptor ß (ERß) in a male-to- female (MtF) population. They suggested that a long ERß 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 ERα, ERß 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, ERα and ß, 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 important hormonal 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.

Sex before the State: Civic Sex, Reproductive Innovations, and Gendered Parental Identity.

Certain changes in the way that states classify people by sex as well as certain reproductive innovations undercut the rationale for state identification of people as male or female in signifying gendered parental relationships to children. At present, people known to the state as men may be genetic mothers to their children; people known to the state as women may be genetic fathers to their children. Synthetic gametes would make it possible for transgender men to be genetically related to children as fathers and transgender women to be genetically related to children as mothers, even if they have otherwise relied on naturally-occurring gametes to be genetic mothers and genetic fathers of children respectively. Synthetic gametes would presumably make it possible for any person to be the genetic father or genetic mother of children, even in a mix-and-match way. Other reproductive innovations will also undercut existing expectations of gendered parental identity. Uterus transplants would uncouple the maternal function of gestation from women, allowing men to share in maternity that way. Extracorporeal gestation ((ExCG)-gestation outside anyone's body-would also undercut the until-now absolute connection between female sex and maternity. In kind, effects such as these-undoing conventionally gendered parenthood-undercut the state's interest in knowing whether parents are male or female in relation to a given child, as against knowing simply whether someone stands in a parental relationship to that child, as a matter of rights and duties.

Phenotype, Sex of Rearing, Gender Re-Assignment, and Response to Medical Treatment in Extended Family Members with a Novel Mutation in the SRD5A2 Gene.

Deficiency of steroid 5-alpha reductase-2 (5ARD2) is an inborn error of metabolism causing a disorder of sexual differentiation. It is caused by a mutation in the SRD5A2 gene in which various mutation types have been reported. Affected individuals have a broad spectrum of presentation ranging from normal female-appearing genitalia, cliteromegaly, microphallus, hypospadias, to completely male-appearing genitalia. We report an extended Emirati family with 11 affected members. The family displayed various phenotypes on presentation leading to different sex of rearing. Some family members were reassigned gender at various stages of life. The index case was born with severe undervirilization with bilaterally palpable gonads and was raised as male from birth. He had a 46,XY karyotype and a high testosterone/dihydrotestosterone ratio. Genetic investigation revealed a novel homozygous deletion of exon 2 of the SRD5A2 gene. Both parents were found to be carriers for the gene deletion. The patient had masculinizing surgery and a course of topical dihydrotestosterone. No beneficial effect of the hormone application was noted over 3 months and the treatment was discontinued. The findings on this kindred indicate that deletion of exon 2 in the SRD5A2 gene causes various degrees of genital ambiguity leading to different sex of rearing in affected family members. Gender reassignment may be done at various ages even in conservative communities like the Gulf region.

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

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.

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.

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.

Twenty years of endocrinologic treatment in transsexualism: analyzing the role of chromosomal analysis and hormonal profiling in the diagnostic work-up.

OBJECTIVE: To demonstrate that adequate pubertal history, physical examination, and a basal hormone profile is sufficient to exclude disorders of sexual development (DSD) in adult transsexuals and that chromosomal analysis could be omitted in cases of unremarkable hormonal profile and pubertal history. DESIGN: Retrospective chart analysis. SETTING: Endocrine outpatient clinic of a psychiatric research institute. PATIENT(S): A total of 475 subjects (302 male-to-female transsexuals [MtF], 173 female-to-male transsexuals [FtM]). Data from 323 (192 MtF/131 FtM) were collected for hormonal and pubertal abnormalities. Information regarding chromosomal analysis was available for 270 patients (165 MtF/105 FtM). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pubertal abnormalities, menstrual cycle, and hormonal irregularities in relation to chromosomal analysis conducted by karyotype or hair root analysis. RESULT(S): In the MtF group, 5.2% of the patients reported pubertal irregularities and 5.7% hormonal abnormalities, and in the FtM group 3.8% and 19.1%, respectively. Overall chromosomal abnormality in both groups was 1.5% (2.9% in the FtM and 0.6% in the MtF group). The aneuploidies found included one gonosomal aneuploidy (45,X[10]/47,XXX[6]/46,XX[98]), two Robertsonian translocations (45,XXder(14;22)(q10;q10)), and one Klinefelter syndrome (47,XXY) that had already been diagnosed in puberty. CONCLUSION(S): Our data show a low incidence of chromosomal abnormalities and thus question routine chromosomal analysis at the baseline evaluation of transsexualism, and suggest that it be considered only in cases of abnormal history or hormonal examination.

Hormone and genetic study in male to female transsexual patients.

BACKGROUND: Data of the literature demonstrated controversial results of a correlation between transsexualism and genetic mutations. AIM: To evaluate the hormone and gene profile of male-female (M-F) transsexual. SUBJECTS AND METHODS: Thirty M-F transsexuals aged 24-39. Seventeen had already undergone sex reassignment surgery, 13 were awaiting. All subjects had been undergoing estrogen and antiandrogen therapy. We studied hormones of the hypothalamus- pituitary-testicular axis, thyroid and adrenal profile, GH basal and after GHRH stimulation, IGF-I. The gene study analyzed SRY, AR, DAX1, SOX9, AZF region of the Y chromosome. RESULTS: Pre-surgery subjects had elevated PRL, reduced testosterone and gonadotropins. Post-surgery subjects showed reduced androgens, a marked increase in LH and FSH and normal PRL. Cortisol and ACTH were similar to reference values in pre- and post-surgery patients. There was a marked increase in the baseline and post-stimulation GH values in 6 of the 13 pre-surgery patients, peaking at T15. IGF-I was similar to reference values in both groups except for one post-surgery patient, whose level was below the normal range. There were no polymorphisms in the amplified gene region for SOX9, and a single nucleotide synonimous polymorphism for DAX1. No statistically significant differences were seen in the mean of CAG repeats between controls and transsexual subjects. SRY gene was present in all subjects. Qualitative analysis of the AZFa, AZFb, and AZFc regions did not reveal any microdeletions in any subject. CONCLUSIONS: This gender disorder does not seem to be associated with any molecular mutations of some of the main genes involved in sexual differentiation.

Is transgendered male androphilia familial in non-Western populations? The case of a Samoan village.

In Western populations, male gender atypicality (i.e., cross-gender behavior and identity) and male androphilia (i.e., sexual attraction to adult males) tend to cluster in particular families. Here, we examined whether this familial clustering effect extended to non-Western populations by examining the genealogical relationships of 17 Samoan transgendered androphilic males, known locally as fa'afafine, who were born in the same rural Samoan village. Specifically, we compared the genealogies of these 17 fa'afafine and those of 17 age-matched comparison males born in the same village. In addition to familial clustering, we examined birth order, sibship sex ratio, and sibship size. The fa'afafine were significantly later born than the comparison males and clustered into five and 16 distinct lineages, respectively, which constituted a statistically significant degree of family clustering among the 17 fa'afafine. Hence, the present study indicated that transgendered male androphilia is familial in this particular Samoan village, thus adding to a growing literature demonstrating that male androphilia and gender atypicality have consistent developmental correlates across populations. Discussion focused on the possible bases of this familial clustering effect and directions for future research.

Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice.

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.