References 2.b: Can genes cause transsexualism?

Aspectos genéticos relacionados ao transexualismo

Original: Transexual é quem não se identifica com o seu sexo de nascimento e que procura adequar ou passou por adequação para o gênero desejado, o que em vários, mas não em todos os casos, envolve transição somática por tratamento hormonal e cirurgia genital (cirurgia de redesignação sexual).

O envolvimento de fatores genéticos no transexualismo é oriundo, sobretudo, de estudos familiares, casos de gêmeos em concordância para a transexualidade e a partir de pesquisas da genética molecular de certos polimorfismos do sistema de genes androgênicos e estrogênicos. O receptor androgênico (RA) é responsável pela diferenciação no córtex cortical e está associado com sua masculinização na adolescência. Foram identificados dois subtipos de receptores estrogênicos: o ERα e o ERβ. O subtipo beta é claramente mais expressivo em várias regiões cerebrais. O receptor ERα está primariamente envolvido na masculinização, enquanto o ERβ tem papel predominante na “defeminização” dos comportamentos sexuais.

Uma pesquisa com 29 mulheres transexuais identificou associação significativa com polimorfismos dos nucleotídeos CA no ERβ (P = 0,03). Em 112 mulheres transexuais foi encontrada uma relação entre polimorfismos do gene longo do AR e transexualismo (P = 0,04).

Duzentos e setenta e três homens transexuais, diferiam, significativamente, dos controles na repetição do tamanho médio do polimorfismo dos ERβ (P = 0,002).

Translation: Transsexuals don’t identify with their birth gender and seek to adopt or transition to their desired gender, which in many but not all cases, involves somatic transition by hormonal treatment and genital surgery (sexual reassignment surgery).

The involvement of genetic factors in transsexualism is derived mainly from family studies, cases of twins in accordance to transsexuality and from research of molecular genetics of certain polymorphisms of androgen and estrogen genes system. The androgen receptor (AR) is responsible for the differentiation in the cortical cortex and is associated with a masculinization in adolescence. Two were identified subtypes of estrogen receptors: the ERα and ERβ. The beta subtype is clearly more significant in various brain regions. The ERα receptor is primarily involved in the masculinization, while ERβ has predominant role in "defeminização" sexual behavior.

A survey of 29 transgender women identified significant association with polymorphisms of CA nucleotides in ERβ (P = 0.03). In 112 transgender women a relationship between polymorphisms throughout the AR gene and transsexualism was found (P = 0.04).

Two hundred and seventy-three transgender men differed significantly from controls on repeat medium size polymorphism of ERβ (P = 0.002).

Author/-s:       Giancarlo SpizzirriI

Publication:     Diagnóstico & Tratamento, 2015

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Short CAG Repeats of the AR Gene Are Associated with Female-to-Male Transsexualism

Background: Female-to-male transsexualism (FtM-T) is considered the most extreme form of gender dysphoria in biological women. Although a multifactorial etiology is probable, reports comprising twin and non-twin sibling transsexuals reinforced the involvement of genetic factors in this disorder. The action of testosterone, directly or by its aromatization, determines virilization in the fetal brain, and this condition might predispose to FtM-T development in female fetus. The polymorphic CAG repeat numbers (nCAG) of the androgen receptor (AR) gene present an inverse correlation with the AR transactivation activity, and longer alleles were previously associated with male-to-female transsexualism.

Objective: to investigate the nCAG of AR in a relatively large cohort of FtM transsexuals followed in a single center.

Patients: Thirty-five FtM transsexuals and 89 non-transsexual female controls were evaluated. All patients had 46, XX karyotype.

Methods: DNA samples were extracted from peripheral leukocytes. The CAG repeat regions were PCR amplified, products were submitted to capillary electrophoresis and analyzed by GeneMapper software. Shorter and longer CAG alleles were defined by ≤ 19 and ≥ 25 repeat numbers, respectively. Student's t and Chi-square tests were used in the statistical analysis.

Results: Eighteen different nCAG alleles were identified in FtM transsexuals (range 13 to 29 repeats) and female controls (range 10 to 29 repeats); the nCAG alleles presented a normal distribution in both groups. Nine controls (10 %) and two FtM transsexuals (5.7 %) were homozygous for the nCAG. Frequency of shorter nCAG alleles was significantly higher in FtM transsexuals than controls, 30 % versus 17.4 %, respectively (p=0.02). Additionally, the frequency of longer nCAG alleles was significantly lower in FtM transsexuals than controls, 13 % versus 18.5 %, respectively (p < 0.02). The nCAG biallelic mean was only marginally significantly lower in FtM transsexuals than controls, 21 ± 2.0 versus 22 ± 2.3, respectively (p = 0.054); however, the sample size effect cannot be ruled out.

Conclusion: Our preliminary findings suggest an influence of higher androgen receptor activity, modulated by the shorter CAG polymorphic tract, in the susceptibility for the female-to-male transsexualism.

Author/-s:       Flávia Siqueira Cunha; Tania A. Bachega; Mariana F. A. Funari; Mirian Yumie Nishi; Maria Helena Palma Sircili; Berenice B. Mendonca; Elaine M. F. Costa; Sorahia Domenice

Publication:     Endocrine Society's 97th Annual Meeting and Expo, 2015

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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.

Author/-s:       Rosa Fernández; Joselyn Cortés-Cortés; Isabel Esteva; Esther Gómez-Gil; Mari Cruz Almaraz; Estefanía Lema; Teresa Rumbo; Juan-Jesús Haro-Mora; Ester Roda; Antonio Guillamón; Eduardo Pásaro

Publication:     The Journal of Sexual Medicine, 2015

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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 ERβ (estrogen receptor β), 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 ERβ; 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 ERβ, 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 ERβ (P = 0.002) but not with respect to the length of the other two studied polymorphisms. The repeat numbers in ERβ 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 ERβ gene and FtM transsexualism. Our data support the finding that ERβ 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 ERβ receptor and thereby encouraging less feminization or a defeminization of the female brain and behavior.

Author/-s:       Rosa Fernández; Isabel Esteva; Esther Gómez-Gil; Teresa Rumbo; Mari Cruz Almaraz; Ester Roda; Juan-Jesús Haro-Mora; Antonio Guillamón; Eduardo Pásaro

Publication:     The Journal of Sexual Medicine, 2013

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This article reviews research on biological and psychosocial factors relevant to the etiology of gender-variant identities. There is evidence for a genetic component of gender-variant identities through studies of twins and other within-family concordance and through studies of specific genes. Evidence that prenatal androgens play a role comes from studies that have examined finger length ratios (2D:4D), prevalence of polycystic ovary syndrome among female-to-male transsexuals, and individuals with intersex and related conditions who are more likely to have reassigned genders. There is also evidence that transsexuals have parts of their brain structure that is typical of the opposite birth-assigned gender. A greater likelihood of non-right-handedness suggests developmental instability may also contribute as a biological factor. There is a greater tendency for persons with gender-variant identities to report childhood abuse and a poor or absent relationship with parents. It is unclear if this is a cause or effect of a gender-variant identity. Parental encouragement of gender-variance is more common among individuals who later develop a gender-variant identity. We conclude that biological factors, especially prenatal androgen levels, play a role in the development of a gender-variant identity and it is likely that psychosocial variables play a role in interaction with these factors.

Author/-s:       Jaimie F. Veale; David E. Clarke; Terri C. Lomax

Publication:     Personality and Individual Differences, 2010

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Background: There is a likely genetic component to transsexualism, and genes involved in sex steroidogenesis are good candidates. We explored the specific hypothesis that male-to-female transsexualism is associated with gene variants responsible for undermasculinization and/or feminization. Specifically, we assessed the role of disease-associated repeat length polymorphisms in the androgen receptor (AR), estrogen receptor β (ERβ), and aromatase (CYP19) genes.

Methods: Subject-control analysis included 112 male-to-female transsexuals and 258 non-transsexual males. Associations and interactions were investigated between CAG repeat length in the AR gene, CA repeat length in the ERβ gene, and TTTA repeat length in the CYP19 gene and male-to-female transsexualism.

Results: A significant association was identified between transsexualism and the AR allele, with transsexuals having longer AR repeat lengths than non-transsexual male control subjects (p = 0.04). No associations for transsexualism were evident in repeat lengths for CYP19 or ERβ genes. Individuals were then classified as short or long for each gene polymorphism on the basis of control median polymorphism lengths in order to further elucidate possible combined effects. No interaction associations between the three genes and transsexualism were identified.

Conclusions: This study provides evidence that male gender identity might be partly mediated through the androgen receptor.

Author/-s:       Lauren Hare; Pascal Bernard; Francisco J. Sánchez; Paul N. Baird; Eric Vilain; Trudy Kennedy; Vincent R. Harley

Publication:     Biological Psychiatry, 2009

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Objective: To assess the association between transsexualism and allele and genotype frequencies of the common cytochrome P450 (CYP) 17 -34 T>C single nucleotide polymorphism (SNP).

Design: Case-control study.

Setting: Academic research institution.

Patient(-s): 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls.

Interventions(-s): Buccal swabs and multiplex polymerase chain reaction on a microarray system.

Main outcome measures(-s): Analysis of the CYP17 -34 T>C SNP.

Result(-s): CYP17 -34 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 55/98 [56 %] and CYP17 C: 43/98 [44 %] versus CYP17 T: 1253/1826 [69 %] and CYP17 C: 573/1826 [31 %], respectively). In accordance, genotype distributions were also different between FtM transsexuals and female controls using a recessive genotype model (CYP17 T/T+T/C: 39/49 [80 %] and C/C 10/49 [20 %] vs. CYP17 T/T+T/C: 821/913 [90 %] and C/C 92/913 [10 %], respectively). The CYP17 -34 T>C allele and genotype distributions were not statistically significantly different between MtF transsexuals and male controls. Of note, the CYP17 -34 T>C allele distribution was gender-specific among controls (CYP17 C: males; 604 of 1512 [40 %] vs. females; 573 of 1826 [31 %]). The MtF transsexuals had an allele distribution equivalent to male controls, whereas FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls.

Conclusion(-s): These data support CYP17 as a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.

Author/-s:       E. K. Bentz; L. A. Hefler; Ulrike Kaufmann; J. C. Huber; A. Kolbus; C. B. Tempfer

Publication:     Fertility and sterility, 2008

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Sex steroid-related genes and male-to-female transsexualism

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and—after aromatase-catalyzed conversion to estradiol—via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERβ gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

Author/-s:       Susanne Henningsson; Lars Westberg; Staffan Nilsson; Bengt Lundström; Lisa Ekselius; Owe Bodlund; Eva Lindström; Monika Hellstrand; Roland Rosmond; Elias Eriksson; Mikael Landén

Publication:     Psychoneuroendocrinology, 2005

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