The CYP17†MspA1 Polymorphism and the Gender Dysphoria.

INTRODUCTION: The A2 allele of the CYP17 MspA1 polymorphism has been linked to higher levels of serum testosterone, progesterone, and estradiol. AIM: To determine whether the CYP17 MspA1 polymorphism is associated with transsexualism. METHODS: We analyzed 151 male-to-female (MtF), 142 female-to-male (FtM), 167 control male, and 168 control female individuals. Fragments that included the mutation were amplified by PCR and digested with MspA1. Our data were compared with the allele/genotype frequencies provided by the 1000 Genomes Data Base, and contrasted with a MEDLINE search of the CYP17 MspA1 polymorphism in the literature. MAIN OUTCOME MEASURES: We investigated the association between transsexualism and the CYP17 MspA1 polymorphism. RESULTS: A2 frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887). This observation concurred with the 1000 Genomes Data Base and the MEDLINE search. CONCLUSION: Our data confirm a sex-dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM > MtF, suggestive of a hypothetical A2 involvement in transsexualism since the allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex.

Association study of ERß, AR, and CYP19A1 genes and MtF transsexualism.

INTRODUCTION: The etiology of male-to-female (MtF) transsexualism is unknown. Both genetic and neurological factors may play an important role. AIM: To investigate the possible influence of the genetic factor on the etiology of MtF transsexualism. METHODS: We carried out a cytogenetic and molecular analysis in 442 MtFs and 473 healthy, age- and geographical origin-matched XY control males. The karyotype was investigated by G-banding and by high-density array in the transsexual group. The molecular analysis involved three tandem variable regions of genes estrogen receptor ß (ERß) (CA tandem repeats in intron 5), androgen receptor (AR) (CAG tandem repeats in exon 1), and CYP19A1 (TTTA tandem repeats in intron 4). The allele and genotype frequencies, after division into short and long alleles, were obtained. MAIN OUTCOME MEASURES: We investigated the association between genotype and transsexualism by performing a molecular analysis of three variable regions of genes ERß, AR, and CYP19A1 in 915 individuals (442 MtFs and 473 control males). RESULTS: Most MtFs showed an unremarkable 46,XY karyotype (97.96%). No specific chromosome aberration was associated with MtF transsexualism, and prevalence of aneuploidy (2.04%) was slightly higher than in the general population. Molecular analyses showed no significant difference in allelic or genotypic distribution of the genes examined between MtFs and controls. Moreover, molecular findings presented no evidence of an association between the sex hormone-related genes (ERß, AR, and CYP19A1) and MtF transsexualism. CONCLUSIONS: The study suggests that the analysis of karyotype provides limited information in these subjects. Variable regions analyzed from ERß, AR, and CYP19A1 are not associated with MtF transsexualism. Nevertheless, this does not exclude other polymorphic regions not analyzed.

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

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 ERß (estrogen receptor ß), 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 ERß; 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 ERß, 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 ERß (P = 0.002) but not with respect to the length of the other two studied polymorphisms. The repeat numbers in ERß 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 ERß gene and FtM transsexualism. Our data support the finding that ERß 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 ERß receptor and thereby encouraging less feminization or a defeminization of the female brain and behavior.