Abstract

Transsexualism is a gender identity disorder with a multifactorial etiology. Both, neurodevelopmental and genetic factors seem to be implicated. The aim of this study was to investigate the possible influence of genetic factors on the etiology of FtM (female to male) and MtF (male to female) transsexualism by performing the molecular analysis of the variable polymorphisms of genes ERβ, AR, CYP19A1 and CYP17A1. We carried out the analysis in 715 transsexuals and 844 controls, geographically and sex-adjusted with the transsexual group. FtMs differed from control females with respect to ERβ (p = 0.002) but not with respect to AR and CYP19A1 genes. The repeat numbers in ERβ were significantly higher in FtMs than in the female control group, and the likelihood of developing transsexualism was higher in the subjects (LL) (odds ratio: 2.001 [1.15-3.46]). Our data support the finding that a functioning ERβ receptor is directly proportional to the size of the analyzed polymorphism, so a greater number of repeats implies greater transcription activation, therefore, an increase in ERβ receptor function, and finally, an increase in defeminization in females. Thus, one could propose that the greater efficiency of the estrogen- receptor complex by a high number of repeats would lead to a reduction in feminization, favoring a defeminization process. Westberg et al., (2001) found that women with relatively few CA repeats of the ERβ gene displayed higher testosterone levels and lower sex steroid hormone-binding globulin levels than those with many CA repeats. The apparent association between a short CA repeat region and high levels of testosterone suggests that this variant of the gene leads to a less active receptor. With regard to MtFs, they did not differ from the male control group with respect to the median length of none of the polymorphisms. Considering the data for categorical variables of S and L alleles, and the genotypes, we did not find any significant values for ERβ, AR or CYP19A1 genes. Regarding CYP17 MspA1, the allelic frequencies differed significantly between FtMs and MtFs (p = 0.041), although it was not sex-dependent in control population. Our data confirm a sex- dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM>MtF, that might suggest a hypothetical involvement of A2 allele in the genetic basis of transsexualism since allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex.