Abstract

In mammals, the brain and gonads begin as bipotential organs that differentiate as male or female during a sensitive perinatal period. In gonads, sex dimorphism is the result of the genetic complement, while, in the brain, it is the result of the exposure to gonadal steroid hormones, testosterone and estrogens. Exposure to testosterone is an essential requirement for masculinization of the brain via aromatization during prenatal life in males, while, in females, feminization of the brain develops under the influence of weak estrogen concentrations. But, sometimes “discordances” arise. Transsexuals are individuals who seek, or have undergone, a social transition from male-to-female (MtF) or female-to-male (FtM) in accordance with their self identity. We analyzed 426 FtM, 588 MtF, 599 control XX women and 728 control XY males recruited from two Units of Gender Identity from Spain. The subjects were diagnosed with Gender Dysphoria (GD) in adults (302.85) according to DSM-5 or with Transsexualism (F64.0) according to ICD-10. The control male and female groups consisted of Caucasians individuals free of any neurological, systemic, or psychiatric illness, as verified in a detailed interview. The polymorphisms analyzed for the ESR1 gene were: (TA)n-ERα (rs3138774), PvuII-ERα (rs2234693) and XbaI-ERα (rs9340799); for the ESR2 gene: (CA)n-ERβ; for the AR gene: (CAG)n-AR; for the aromatase CYP19A1 gene: (TTTA)n-CYP19A1; and for the CYP17A1 gene: MspA1-CYP17A1 (rs743572). Analyses were performed using SPSS® 23.0, with a p value below 0.05 being taken as significant. The mean number of tandem repeats was analyzed by the Mann–Whitney U-test. Allele and genotype frequencies were analyzed by chi-squared test. Association and linkage disequilibrium analyses were performed using SNPStats software. The main finding in the MtF population was that the (CAG)n-AR polymorphism is involved in the expression of GD, in a necessary but not sufficient manner. AR must interact with specific ERβ genotypes or in a specific combination with the XbaI-ERα and the CYP19A1 polymorphisms. Thus, there is high risk for GD when the short (S) allele for AR is associated with the L/L genotype for ERβ, and inversely, when the long (L) allele for AR is associated with the S/S genotype for ERβ. Our data indicate estrogen receptor involvement as a key element in brain sexual differentiation in XY and XX populations. The fact that the AR is not associated to a brain phenotype that presents masculine traits, supports the role of the estrogen receptor in normative masculinization, and the probability that human female brain differentiation is actively sexually differentiated.