Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria

J Sex Med. 2017 Mar;14(3):464-472. doi: 10.1016/j.jsxm.2016.12.234. Epub 2017 Jan 20.


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 β 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.

Keywords: Estrogen Receptor α; Estrogen Receptor β; Gender Dysphoria; rs2234693; rs3138774; rs9340799.

MeSH terms

  • Adult
  • Alleles
  • Estrogen Receptor alpha / genetics*
  • Female
  • Gender Dysphoria / genetics*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Genetic*


  • ESR1 protein, human
  • Estrogen Receptor alpha