Abstract

Gender Dysphoria (GD) (DSM-5) is characterized by a marked incongruence between gender and biological sex (ICD-10). They have undergone a social transition from male-to-female (MtF) or female-to-male (FtM), and do not constitute a homogeneous group according to the onset of dysphoria and the sexual orientation (Blanchard 1989). DNA polymorphisms of genes involved in steroidogenesis have been associated with transsexualism. However, the inconsistences between reports (Henningsson et al. 2005; Hare et al. 2009; Ujike et al. 2009; Fernández et al. 2014 a,b) might be due to the stratification of the samples. We studied the implication of (CA)n-ERβ, XbaI-ERα, (CAG)n-AR and (TTTA)n-CYP19A1 polymorphisms in an early onset sample of 549 androphilic MtFs, 425 gynephilic FtMs, 728 male and 599 female controls. Moreover, because it is unknown whether androgen, estrogen and aromatase genotypes interact with each other in the genesis of gender, we also analyzed the cross interactions between the four polymorphisms. Results: Our data showed that specific allele and genotype combinations of ERβ, ERα, CYP19A1 and AR are implicated in the genesis of transsexualism. MtF gender development is associated to the AR which must be accompanied by ERβ. An inverse allele interaction between ERβ and AR is characteristic of the MtF population. ERβ and ERα polymorphisms are also associated with transsexualism in the FtM population, although there was no interaction between these polymorphisms. Our data showed that ERs play a key role in typical human gender and brain development and differentiation. This is an important theoretical point since it was believed that male human brain differentiation depended on AR (Puts & Motta-Mena, 2018; Swaab, 2004). Conclusions: Key receptors implicated in sexual differentiation of the brain have a specific allele combination for ERβ, ERα and AR in the MtF population, whose gender differentiation is associated with a specific genotypic combination of ERs and AR polymorphisms. In addition, FtM gender is associated with specific polymorphisms of the ERβ and ERα receptors. In humans, ERα and ERβ play a key role in the typical gender development and sexual differentiation of the brain.