Effects of sex hormone treatment on white matter microstructure in individuals with gender dysphoria
Introduction
The modulatory role sex hormones play in animals and humans extends beyond the regulation of reproductive activity and the determination of biological sex. In fact, sex hormones strongly impact on the entirety of our mental activities including planning, thinking and emotional processing. Therefore, it comes as no surprise that neuroscience has accumulated an increased amount of evidence indicating that sex hormones modulate brain structures and their associated functions. Sex hormones such as estradiol and testosterone are pivotal in mediating brain development via regulating the physiology of developing neurons, neural pruning and axonal as well as dendritic spine growth (McCarthy, 2008). Moreover, aromatized testosterone is believed to masculinize the rodent brain in prenatal and early infant brain development (Bao and Swaab, 2011). Yet, recent evidence, also in complete androgen insensitivity syndrome patients, indicates that testosterone itself influences structural brain properties via activation of the androgen receptor (Bao and Swaab, 2011, Perrin et al., 2008, Pesaresi et al., 2015). Axon diameter and axonal transport in particular seem to be influenced by androgens in a dose-dependent manner (Pesaresi et al., 2015); an effect that is likely reflected in white matter (WM) microstructural changes when investigated with suitable MRI sequences.
Studying the effects of sex hormones on WM microstructure in humans in vivo is a challenging endeavor and reaches ethical limits when truly experimental approaches are applied. Consequently, researchers have often contented themselves by investigating such influences indirectly via a simple comparison between the sexes (Chou et al., 2011, Menzler et al., 2011). Sometimes these comparisons are also aimed to differentiate sex from gender, with promising results (Hahn et al., 2014, Kranz et al., 2014, Rametti et al., 2011a, Rametti et al., 2011b) while others chose to correlate endogenous hormone plasma levels with neuroimaging variables at different stages of life (Herting et al., 2012, Menzies et al., 2015).
However, the experimental “silver bullet” in the investigation of hormone effects – the exogenous administration of physiologically meaningful amounts of sex hormones for a sufficient period of time – is only possible in humans who are seeking hormonal treatment, such as transgender individuals, or postmenopausal women. In particular, transgender individuals seeking hormone replacement therapy and sex reassignment surgery offer the unique opportunity to disentangle the effects of hormones from simple sex differences and few studies have applied such an approach. In a recent study of Female-to-Male transgender individuals (FtM) we demonstrated that longitudinal changes in testosterone after 4 weeks of treatment were negatively associated with gray matter volume in Broca's and Wernicke's area (Hahn et al., 2016). Furthermore, we observed an inverse relationship between testosterone increases and mean diffusivity (MD) of the structural connection between the two regions, whereas the corresponding functional connectivity was positively associated with testosterone plasma level changes. Such effects of androgenization in FtMs were also investigated in a Spanish study (Rametti et al., 2012). Focusing on WM microstructure using diffusion tensor imaging (DTI), authors observed increased fractional anisotropy (FA) in the right corticospinal tract (CST) and superior longitudinal fasciculus (SLF) after at least seven months of treatment. Other diffusivity parameters such as MD were not evaluated. Investigating a potential influence of estrogen and anti-androgen treatment in Male-to-Female transgender individuals (MtF) or the temporal course of such an influence warrants additional research.
Here, our objective was to investigate the effects of hormone replacement therapy in FtMs and MtFs at four weeks and at four months of continued treatment in comparison to female and male controls (FC, MC, respectively). We hypothesized that testosterone treatment in FtMs increases FA and decreases MD in a time-dependent manner, whereas estrogen and anti-androgen treatment in MtFs shows inverse effects.
Section snippets
Subjects
A total sample of n=77, consisting of 44 individuals with gender dysphoria (29 FtM, 15 MtF) and 33 controls (18 FC and 15 MC) were included. Data from these subjects have been published previously (Hahn et al., 2016, Kranz et al., 2014). Subject's age was comparable between groups (FtM: 26.79±5.93, MtF: 28.07±7.54, FC: 25.78±6.17, MC: 28.60±6.17, mean±SD, p>0.05, ANOVA). FtMs/MtFs were diagnosed using DSM-IV (text revision) and ICD-10 in several semi-structured, sociodemographic, clinical and
Hormone treatment
Estradiol and testosterone levels at each time point were not normally distributed for the four groups (p<0.05), whereas plasma level changes between time points were normally distributed (assessed using Kolmogorov-Smirnov test and visual inspection). As expected, testosterone plasma levels significantly increased in FtM due to androgen treatment. Conversely, anti-androgen and estrogen treatment in MtF led to significant decreases of testosterone and increases of estradiol plasma levels
Discussion
The aim of this study was to examine the influence of sex hormones on white matter microstructure using DTI in individuals with gender dysphoria undergoing HRT. We found that hormone replacement therapy had opposing effects on white matter tracts. FA increases and MD reductions were found in FtMs, whereas FA decreases and MD increases were found in MtFs after 4 months of treatment. To our knowledge, only one published study has investigated treatment effects in transgender individuals on white
Conclusion
In summary, by investigating the effects of hormone replacement therapy in female-to-male and male-to-female transgender individuals, we observed androgenization-related reductions in mean diffusivity and increases in fractional anisotropy. We also observed feminization-related increases in mean diffusivity and reductions in fractional anisotropy, although effects were scattered and not located in the same regions. The results indicate that sex hormones are a central modulator for white matter
Conflict of interest
The authors declare no conflict of interest in the context of this study.
Acknowledgements
We thank P. Baldinger, A. Höflich, C. Kraus, T. Vanicek, A. Kautzky, G. Gryglewski, M. Spies, E. Winkler, D. Winkler, U. Moser, E. Akimova, E.K. Tempfer-Bentz, and C. Tempfer for their medical support. We thank M. Küblböck for technical support and A.C. Pollock for native English editing. We are especially grateful to all transgender individuals for participating in this study. This work was supported by the Austrian Science Fund (FWF) grant numbers P 23021 and KLI 504 to R.L.
References (29)
- et al.
Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders
Front. Neuroendocrinol.
(2011) - et al.
Sex-linked white matter microstructure of the social and analytic brain
NeuroImage
(2011) - et al.
Novel cellular phenotypes and subcellular sites for androgen action in the forebrain
Neuroscience
(2006) - et al.
High-dose testosterone treatment increases serotonin transporter binding in transgender people
Biol. Psychiatry
(2015) - et al.
The effects of puberty on white matter development in boys
Dev. Cogn. Neurosci.
(2015) - et al.
Men and women are different: diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum
NeuroImage
(2011) - et al.
Axon diameter and axonal transport: in vivo and in vitro effects of androgens
NeuroImage
(2015) - et al.
White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study
J. Psychiatr. Res.
(2011) - et al.
The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study
J. Psychiatr. Res.
(2011) - et al.
Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study
Psychoneuroendocrinology
(2012)