Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals

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Abstract

Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals.

fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) = 3.7, p = 0.08), and total language activity was correlated to post-treatment estradiol levels (rho = 0.54, p = 0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12) = 1.47, p = 0.25). Activation during mental rotation did not increase during treatment (F(1,12) = 0.54, p = 0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho = 0.64, p = 0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.

Introduction

Sex hormones (estrogens and androgens) may affect cognitive functions both in males and females. For example, Aleman et al. (2004) found significantly improved performance on mental rotation tasks in healthy young females after administration of a single dose of testosterone. In parallel, Cherrier et al. (2003) described improvement on spatial memory in hypogonadal males receiving testosterone replacement therapy. In contrast, subjects treated with androgen blockade for prostate cancer showed a decrease in spatial abilities but increased performance on verbal memory (Cherrier et al., 2001). Hampson and Kimura (1988) found improved spatial skills in healthy women during the menstrual phase, when estrogen level is low and improved verbal skills in the midluteal phase, when estrogen level is high. Slabbekoorn et al. (1999) described decreased performance on verbal fluency tasks and increased performance on mental rotation tasks in female-to-male transsexuals treated with androgens, while male-to-female transsexuals treated with androgen blockade and estrogen addition showed the opposite changes in cognitive performance (but see van Goozen et al., 2002). These results suggest that androgen administration improves performance on mental rotation tests with decreasing performance on verbal fluency tests, whereas anti-androgen and estrogen administration appears to induce the opposite effects. Precisely how sex steroids act on the brain to affect performance on cognitive tasks is currently unclear. Animal studies found effects of estrogen on synaptic density and transmission. For example, Yankova et al. (2001) demonstrated that increased estrogen concentrations induce synaptogenesis and alterations in synaptic transmission in hippocampal pyramidal cells in female rats. In the human brain, no analogues of these sex steroid-induced neural changes have been described.

Both language and spatial functions have an asymmetrical cerebral representation, with language activation predominantly in the left hemisphere and spatial activation predominantly in the right hemisphere (Kimura, 2000). Several dichotic listening and visual half-field studies have suggested that estrogens decrease cerebral lateralization for language (Herman et al., 1993, Wisniewski et al., 2005) while androgens are associated with increased language lateralization (Gadea et al., 2003). Low degrees of language lateralization are thought to induce competition between verbal and spatial functions in the right hemisphere, leading to reduced spatial functioning (Levy, 1969). However, evidence for this mechanism is lacking. Thus, though several studies have explored the effects of sex steroids on performance on verbal and spatial tasks (reviewed by Collear and Hines, 1995), the effects of sex hormones on the neural representation of these functions are unclear.

In this study, we aimed to investigate the effects of inversing the sex steroids milieu on cerebral activation and lateralization of language and spatial functioning. For this purpose, we obtained functional Magnetic Resonance Imaging (fMRI) scans of both male-to-female transsexuals and female-to-male transsexuals, at baseline and after three months of cross-sex hormone administration.

Section snippets

Subjects

Subjects were eight male-to-female transsexuals (22 ± 3 years old, and education of 10 ± 3 years) and six female-to-male transsexuals (29 ± 9 years old, education of 12 ± 3 years) eligible for cross-sex hormone treatment. All subjects gave their informed consent to the research protocol which had been approved by the ethical review board of the institution. They were scanned a few days before the start of hormonal treatment and again, after approximately 3 months of hormonal treatment. Male-to-female

Hormonal status

The mean serum levels of testosterone and 17β-estradiol are shown in Table 1 at the day of the first MRI scan (i.e. before hormonal treatment) and at the day of the second scan (i.e. after three months of sex steroid treatment). In the female-to-male transsexuals, the mean testosterone concentration in blood was significantly higher at the second scan, as compared to the first (t =  2.8, df = 5, p = 0.04), while the 17β-estradiol concentration showed no significant change (t =  0.3, df = 5, p = 0.8). In

Discussion

This is the first study to investigate changes in functional cerebral activation and lateralization in human subjects before and after cross-sex hormone treatment inducing an endocrine milieu of the opposite sex. The total language-related activation was lower after treatment compared to baseline and correlated to post-treatment serum estradiol levels. However, language lateralization remained highly stable, with a high degree of correlation between the first and second scan (rho = 0.87). For

Role of funding source

There was no specific funding for this project.

Contributors

Authors Ramsey, Kahn and Cohen-Kettenis designed the study and wrote the protocol. Author van Raalten introduced the patients into the scanner and performed the actual scans. Author Sommer, van der Veer and Ramsey undertook the statistical analysis, and Sommer wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

None of the authors has any interest that could inappropriately influence, or be perceived to influence, their work.

Acknowledgement

The authors would like to thank Dr. E.J. Giltay for his thoughtful comments.

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