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

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 172; pp. 20 - 28
• Main Authors: Aranda, Gloria, Fernández-Rebollo, Eduardo, Pradas-Juni, Marta, Hanzu, Felicia Alexandra, Kalko, Susana G., Halperin, Irene, Mora, Mireia
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2017; Elsevier BV
• Subjects: Adolescent; Adult; Androgen receptor; Androgen receptors; Anthropometry; Cross-sex hormone treatment; Cyproterone Acetate - therapeutic use; DNA methylation; DNA Methylation - drug effects; Drug Administration Schedule; Endocrine therapy; Epigenesis, Genetic; Epigenetics; Estradiol - analogs & derivatives; Estradiol - therapeutic use; Estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Female; Follicle Stimulating Hormone - genetics; Follicle Stimulating Hormone - metabolism; Gender; Gender dysphoria; Gender Dysphoria - drug therapy; Gender Dysphoria - genetics; Gender Dysphoria - metabolism; Gender Dysphoria - pathology; Gene expression; Humans; Luteinizing Hormone - genetics; Luteinizing Hormone - metabolism; Male; MicroRNAs; Polymerase chain reaction; Prolactin - genetics; Prolactin - metabolism; Promoter Regions, Genetic; Prospective Studies; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Reverse transcription; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex Hormone-Binding Globulin; Signal Transduction; Steroid hormones; Steroids; Studies; Testosterone - analogs & derivatives; Testosterone - therapeutic use; Xenoestrogens; Estrogen receptor; Gender dysphoria; Cross-sex hormone treatment; Androgen receptor
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2017.05.010

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