Xenogenders

NCBI

Archives of Sexual Behavior

Springer

A Review of the Status of Brain Structure Research in Transsexualism

Antonio Guillamon, Carme Junque, and Esther Gómez-Gil
Additional article information

Abstract

The present review focuses on the brain structure of male-to-female (MtF) and female-to-male (FtM) homosexual transsexuals before and after cross-sex hormone treatment as shown by in vivo neuroimaging techniques. Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females. These phenotypes have theoretical implications for brain intersexuality, asymmetry, and body perception in transsexuals as well as for Blanchard’s hypothesis on sexual orientation in homosexual MtFs. Falling within the aegis of the neurohormonal theory of sex differences, we hypothesize that cortical differences between homosexual MtFs and FtMs and male and female controls are due to differently timed cortical thinning in different regions for each group. Cross-sex hormone studies have reported marked effects of the treatment on MtF and FtM brains. Their results are used to discuss the early postmortem histological studies of the MtF brain.

Keywords: Transsexualism, Sex differences, Gender identity, Gender dysphoria, Cross-sex hormone treatment, Magnetic resonance imaging

Introduction

Transsexuals seek or have undergone a social transition from male to female (MtF) or female to male (FtM), a transition that in many, but not all, cases also involves a somatic transition by cross-sex hormone treatment and genital surgery (American Psychiatric Association, 2013; Meyer-Bahlburg, 2010, 2013).
Although the etiology of transsexualism is unknown, biological and environmental factors have been suggested to contribute to gender identity variations (Cohen-Kettenis & Gooren, 1999; Savic, Garcia-Falgueras, & Swaab, 2010; Lawrence & Zucker, 2014). Biological causes for gender dysphoria (GD) are supported by studies on familial groups (Gomez-Gil et al., 2010; Green, 2000), birth order (Blanchard & Sheridan, 1992; Blanchard, Zucker, Cohen-Kettenis, Gooren, & Bailey, 1996; Gomez-Gil et al., 2011; VanderLaan, Blanchard, Wood, Garzon, & Zucker, 2015; Vasey & VanderLaan, 2007), and twins (McKee, Roback, & Hollender, 1976; Zucker & Bradley, 1995). A review of the literature of twins concordant and discordant for GD suggests a role for genetics in the development of GD (Heylens et al., 2012). Molecular genetics have been used to analyze peripheral sex steroid-related polymorphisms in steroid receptors or steroid enzyme genes (Fernandez et al., 2014a, 2014b; Hare et al., 2009; Henningsson et al., 2005; Ujike et al., 2009). Research on prenatal androgen exposure markers has provided some evidence of transsexual differences based on the 2D:4D ratio (Schneider, Pickel & Stalla, 2006; Wallien, Zucker, Steensma & Cohen-Kettenis, 2008). The findings from all the above studies suggest that genetic factors could influence brain and behavioral phenotypes.
In regard to environmental variables, parental and family factors have been reviewed (Lawrence & Zucker, 2014); parental influences seem to be a contributing factor to the development of GID (Cohen-Kettenis & Gooren, 1999) and play a role in social gender transitioning (Steensma, McGuire, Kreukels, Beekman, & Cohen-Kettenis, 2013).
With respect to the developmental course of GD and sexual orientation, DSM-5 indicates that in both natally male and female children showing persistence, almost all are sexually attracted to individuals of their natal sex. Moreover, there are two broad trajectories for the development of GD: early-onset and late-onset. Early-onset GD starts in childhood and continues into adolescence and adulthood, while late-onset GD begins around puberty or even much later in life. Adolescent and adult natal males with early onset of GD are almost always androphilic, while most with a late onset are gynephilic. In natal females, the most common course is early-onset GD; they are almost always gynephilic, while the few with late-onset GD are usually androphilic (APA, 2013, pp. 455–456). Although DSM-5 criteria no longer include diagnostic subtyping by sexual orientation, early and late GD onset and sexual orientation have been stressed by those authors who distinguish two subtypes of MtFs and FtMs (Blanchard, 1989a, 1989b; Smith, van Goozen, Kuiper, & Cohen-Kettenis, 2005). Blanchard, taking into account the sex chromosomes at birth, has named androphilic MtFs homosexual and gynephilic MtFs nonhomosexual (Blanchard, 1989a, 1989b). However, Gooren had reservations about the use of the terms “homo”- and “nonhomosexual” because MtFs do not view themselves as homosexuals, considering themselves women in their sexual interaction with men (Gooren, 2006). The fact that two subtypes of MtFs and FtMs can be distinguished has important theoretical and clinical implications for the etiology of transsexualism (Blanchard, 2005). Consequently, distinctions between early- and late-onset GD and androphilic and gynephilic sexual orientation become essential when approaching the brain of transsexuals. Moreover, predictions for brain differences between MtF subtypes have been advanced in light of this distinction (Blanchard, 2008).
Brain sex differences have been used to study transsexuality. The approach was based on previous reports regarding the existence of morphological sex differences in the mammalian brain. It seems logical to compare the brains of MtFs and FtMs with brains from both male and female controls.
The early brain studies on transsexuality, directed toward the hypothalamus and the extended amygdala in postmortem human specimens, reported that the central part of the bed nucleus of the stria terminalis (BSTc) was feminine in MtFs (Zhou, Hofman, Gooren, & Swaab, 1995). More recently, a few groups have explored how brain sex differences are expressed in vivo in the brain of MtFs and FtMs using neuroimaging techniques.
This review focuses on the brain structure of early-onset GD androphilic (homosexual) MtFs and early-onset GD gynephilic (homosexual) FtMs. The early onset of GD and sexual orientation are key points in the following analysis. Our main aims are to (1) address the structural phenotype of the brain in homosexual MtFs and FtMs before cross-sex hormone treatment; (2) discuss these brain phenotypes in the light of the neurohormonal theory of sexual differentiation of the brain; (3) describe the effects of cross-sex hormone treatment on the structure of the brain; and (4) analyze the histological postmortem studies in light of the in vivo neuroimaging results. Investigating these objectives has suggested an explanatory hypothesis on gender. In approaching these objectives, we encountered several difficulties. The main one is the scant number of published MRI studies on the brain of transsexuals; this scarcity is more extreme in regard to nonhomosexual MtFs and FtMs. Moreover, some studies do not report sexual orientation or mix homosexual and nonhomosexual subjects.