Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction

Fernández, Rosa; Guillamón, Antonio; Cortés-Cortés, Joselyn; Gómez‐Gil, Esther; Jácome, Amalia; Esteva, Isabel; Almaraz, MariCruz; Mora, Mireia; Aranda, Gloria; Pásaro, Eduardo

doi:10.1016/j.psyneuen.2018.07.032

Cited by 54 publications

(58 citation statements)

References 34 publications

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“…On the other hand, these data are also consistent with our previous genetic data on the participation of the ESR1 gene in the genetic basis of gender dysphoria. 30,31 Here, we propose that variations in RIII methylation are related to the process of masculinization of the brain and, therefore, to the etiology of gender incongruence.…”

Section: Discussionmentioning

confidence: 99%

“…It might be related to neurodevelopmental processes of the brain 19,21 probably as a consequence of a genetic vulnerability 22e32 that implicates variations in the nuclear receptor's sensitivity to their ligand. In our previous studies, 31 we first proposed a hypothetic genetic model based on ERa, ERb, and AR allele combinations. We suggested that different allele combinations could modulate the sensitivity and therefore the efficiency of the ER to the ligand, and thus, different ERa, ERb, and AR allele combinations may play a significant role in brain masculinization.…”

Section: Introductionmentioning

confidence: 99%

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Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Fernández

Ramírez

Gómez‐Gil

et al. 2020

The Journal of Sexual Medicine

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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 a (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 (À1,188 to À790 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

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Fernández

Ramírez

Gómez‐Gil

et al. 2020

The Journal of Sexual Medicine

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“…The TG biological underlining is not well understood. Genetically, it appears that interplay between sex steroid receptor polymorphisms, particularly those of androgen and estrogen, which are associated with TG [3]. Yet the RYR3 variant was identified in the Han Chinese population with GD [4] and CYP17 single nucleotide polymorphism was linked to female-to-male TGism [5] whereas a common SRD5A2 polymorphism has been shown recently to be benign in TGism (ClinicalTrials.gov Identifier: NCT00435513).…”

Section: Introductionmentioning

confidence: 99%

A Rare Case of 83-Year-Old Transgender Female: Can Thyroid Hormone Deficiency Be Involved in Transgenderism and Gender Dysphoria?

Frolov¹,

Polcaro²,

Lawson³

et al. 2020

ASM

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In the current report, we describe an 83-year-old biological male who selfidentified as a female by legally changing his first and middle names to female ones and whose death certificate states his sex as a female. The medical history of this individual indicated complete penectomy without further specification. Postmortem physical examination revealed an absence of penis with a large scrotum, transposed urethral orifice, and small testes. The histological analysis of the testes identified abnormal epithelium in the seminiferous tubules that lacked germ and Sertoli cells as well as the interstitium without Leydig cells present. The exome sequencing of the individual's DNA using the Next Generation Sequencing (NGS) Illumina platform revealed no genetic variants associated with either penile or urethral cancer that could have explained the complete penectomy, but pointed toward a potentially impaired production of T3 and T4 thyroid hormones which could account for the observed testicular malformation. Overall, the data obtained raise an important question as to whether the thyroid hormone axis could be an important part of the hormonal architecture supporting male sexual behavior.An 83-year-old TF cadaver was received through Saint Louis University (SLU) School of Medicine Gift of Body Program from an individual who had given his written informed consent. The body was embalmed through the right femoral artery with a mixture of water and a solution (2:1) containing 33.3% glycerin, 28.8% phenol, 4.6% formaldehyde, and 33.3% methanol. Anatomical DissectionThe cadaveric body was dissected according to [11].A. Frolov et al. Histological AnalysisTesticular tissue was procured from the embalmed body. Tissue fixation, paraffin embedding, sectioning, and staining with hematoxylin & eosin were performed by Research Microscopy and Histology Core, Department of Pathology, Saint Louis University (SLU) School of Medicine according to the standardized procedures. Images were captured on Olympus 41BX-EPI microscope equipped with the 10× UPlan FL N, 20× LUCPlan FL, and 40× UPlan FL N objectives. The data acquisition and image analysis were performed by using CellSens Standard software. Bone DensitometryBone density of the lumbar spine and left femoral neck of the embalmed body was measured in triplicates using certified Hologic QDR-4500 X-ray Bone Densitometer in the dual energy X-ray absorptiometry (DEXA) mode following the manufacturer's protocol. The respective average T-score values were used throughout the text. LimitationsThe deleterious (pathologic) genetic variants were identified by the exome sequencing of a single proband. The high scientific value of a single proband approach to unique human cases has been recently demonstrated [27].

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“…The prevalence GI has increased in recent years, possibly because of the increased visibility and destigmatization of this condition. A recent study reported that 4.6 people per 100,000 hav (Fernández, et al, 2018)e GI, with about 6.8 males-to-females (MtFs) and 2.6 females-to-males (FtMs) per 100,000 people .…”

Section: Introductionmentioning

confidence: 99%

“…The etiology of GI is uncertain; however interactions among biological, environmental, and cultural factors are likely to be important (Rosenthal, 2014). Recent research suggested that polymorphisms of estrogen and testosterone receptors and of enzymes involved in the metabolism of these hormones have roles in the etiology of GI (Kudwa, Michopoulos, Gatewood, & Rissman, 2006;Raznahan, et al, 2010;Henningsson, et al, 2005;Fernández, et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Características clínicas e sociodemográficas de uma população com disforia/incongruência de gênero

Okano¹

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Aos meus amigos, aos familiares e a todos que estiveram envolvidos de alguma forma no desenvolvimento desta dissertação. Aos professores. À Dra. Lúcia Alves da Silva Lara, cuja dedicação ao estudo da Sexualidade Humana me tornou um apaixonado pelo tema, e por seu empenho em me trilhar nos caminhos da minha formação pessoal, não só como mestrando, mas como um especialista nesta área de atuação da Sexologia. Ao prof. Omero Benedicto Poli Neto e a prof. Giordana Campos Braga pela clarividência diante dos desafios da estatística e da metodologia científica, tão essenciais a minha formação. À minha família, por apoiar minhas decisões e por estarem ao meu lado nos momentos de alegria e nos momentos de desespero. Aos meus pais, Sérgio e Cristina, por todo carinho e dedicação durante a trajetória da vida; ao meu irmão, Guilherme, pelo incentivo e companheirismo; à minha família de ribeirão, Sarah e Gabriele, e à Thais, ombro direito de sofrimento conjunto nesta trajetória, e ao meu querido Matheus pela paciência e cumplicidade durante esse trabalho. Aos amigos, que são muitos e seria desonroso citá-los e, por ventura, me esquecer de alguém. E, finalmente, o presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) por meio do Programa de Excelência Acadêmica (PROEX). RESUMO OKANO, Sergio Henrique Pires Okano. Características clínicas e sociodemográficas de uma população com disforia/incongruência de gênero.

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Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction

Abstract: ERβ plays a key role in human gender differentiation in males and females.

Cited by 54 publications

References 34 publications

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

A Rare Case of 83-Year-Old Transgender Female: Can Thyroid Hormone Deficiency Be Involved in Transgenderism and Gender Dysphoria?

Características clínicas e sociodemográficas de uma população com disforia/incongruência de gênero

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