Effect of sex steroids on the human brain

Background: Converging evidence indicates that sex steroid hormones influence brain function and structure. Several studies show the strong influence of sex steroid hormones on neuronal response to emotional and cognitive demanding stimuli. Recent studies also indicate sex steroid hormones to influence brain structure and connectivity. The ultrahigh-field MRI study proposed gives us the unique opportunity to measure changes in brain function and structure induced by long-term opposite-sex steroid hormone administration. Objectives of the study: 1. to prove the influence of high-dose, long-term opposite-sex steroid hormone treatment on functional brain response in transsexuals. 2. to investigate the influence of hormone treatment on resting state functional connectivity and brain morphology. 3. to investigate differences between transsexuals and healthy control subjects in brain function and functional connectivity, brain morphology and structural connectivity. Study design: Single-blind, longitudinal study. Transsexuals and healthy control subjects will undergo three 7 Tesla ultrahigh-field MRI scan sessions: 1. baseline (before hormone treatment), 2. after 4 weeks of treatment and 3. after 4 months of treatment. We propose an overall study duration of 36 months. Materials and Methods: Functional and structural MRI measurements will be performed on a 7 Tesla scanner providing high sensitivity data with high spatial and temporal resolution. Each subject will perform six different fMRI paradigms: (I-III) three emotion paradigms; (IV-V) two cognitive paradigms and (VI) a motor paradigm. Furthermore, we will assess resting-state functional connectivity and use diffusion tensor imaging (DTI) to obtain anatomical connectivity measures. Structural data will be examined using voxel-based morphometry (VBM) and region of interest based morphometry. Study population: 20 healthy female-to-male (FtM), 20 healthy male-to-female (MtF) transsexuals (aged 18-50), free of hormone-medication at baseline; 40 healthy controls, matched for sex, age and sexual orientation. Relevance and implications of the study: This will be the first imaging study to investigate the effects of high-dose, long-term opposite-sex hormones on task-specific brain activation in both sexes using 7 Tesla ultrahigh-field MRI. This study will also be the first to investigate differences between healthy controls and transsexuals and the influence of opposite-sex hormones on resting state functional connectivity, diffusion weighted connectivity and on whole-brain morphology using VBM. The results of this study will provide essential data for improved understanding of neural sex differences associated with differences in hormonal states in humans. In addition, this study will shed new light on sexual differentiation of the brain in transsexuals that possibly contrasts with that of the genetic and physical characteristics of sex.

Sex steroid hormones influence how we feel, think and behave. In this basic neuro-scientific project we showed that brain function as well as brain structure of the adult human brain is strongly influenced by high dosages of testosterone and estradiol. Using modern neuroimaging techniques such as 7 Tesla ultrahigh-field functional magnetic resonance imaging our study examined the influence of high-dosage cross-sex steroid hormone treatment in transsexual subjects. This experimental approach provided us the unique opportunity to investigate hormonal influences on the biological basis of language processing, on risk behavior, spatial cognition and impulsivity. Comparing transsexual subjects with controls further allowed us to probe neural correlates of gender identity and biological sex.Volumetric analyses showed that an increase of blood testosterone levels after four weeks of hormone therapy was related to a decrease of cortical volumes in Wernickes and Brocas area, two brain regions that are central for speech perception and speech production, respectively. Similarly, the connection between the two regions was highly influenced by testosterone, indicating that testosterone modulates language processing via structural modifications of underlying white and gray matter structures.A detailed analysis of the microstructure of brains white matter showed that females and males greatly differ in their regional connections between brain regions. Interestingly, transsexual subjects exhibited values in between both control groups. This finding suggests that gender identity is partly reflected by features within the white matter microstructure. On the other hand, a graph theoretical analysis of structural connections revealed unique characteristics of transsexuals that separated both patient groups from control subjects. A further analysis of functional connections between brain regions using 7 Tesla fMRI showed that brain connections exhibit great inter-individual variability, a finding that can be interpreted as a functional correlate of individual diversity in the brains network economy. A number of further analyses confirmed strong influences of sex hormone treatment on the neuronal correlates of impulsivity, risk taking behavior, empathy and spatial cognition. Moreover, investigations of behavioral data showed hormone effects on empathy and pain perception. The project thus widens our basic neuroscientific understanding of the impact of sex steroids on human brain function, structure and connectivity. Furthermore, the project has also clinical relevance because many psychiatric disorders and symptoms are strongly connected to sex steroids. Thus, our research contributes to the elucidation of the neuronal basis for the proposed connection between sex steroids and cognitive, as well as mood symptoms.