The (CA)n polymorphism of ERβ gene is associated with FtM transsexualism

J Sex Med. 2014 Mar;11(3):720-8. doi: 10.1111/jsm.12398. Epub 2013 Nov 26.


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.

Keywords: Androgen Receptor; Aromatase; Estrogen Receptor; Gender Identity Disorder; Genetic Causes of Gender Identity Disorder; Transsexualism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Aromatase / genetics
  • Case-Control Studies
  • Estrogen Receptor beta / genetics*
  • Female
  • Genotype
  • Humans
  • Polymorphism, Genetic / genetics*
  • Receptors, Androgen / genetics
  • Transsexualism / genetics*


  • AR protein, human
  • Estrogen Receptor beta
  • Receptors, Androgen
  • Aromatase
  • CYP19A1 protein, human