THE BRAIN ON HORMONES: EFFECTS OF GENDER-AFFIRMING HORMONE THERAPY ON GRAY MATTER DENSITY AND MICROSTRUCTURE
Authors: Handschuh *Patricia Anna , Reed Murray Bruce , Spies Marie , Kaufmann Ulrike , Kloebl Manfred , Spurny-Dworak Benjamin , Kranz Georg S , Lanzenberger Rupert 
Published: February 2025

Abstract

Background
Sex-specific differences in brain morphology [1] and specifically gray matter (GM) volume [2, 3], density (GMD) and microstructure (GMM) [4] were shown in several neuroimaging studies. Sex steroids were suggested to have a significant impact on these sex-dependent GM characteristics [5, 6]. Given the accurate monitoring of peripheral sex steroid levels in transgender individuals receiving gender-affirming hormone therapy (GHT), the effect of sex hormones on structural alterations of the brain can be reliably quantified in these cohorts via magnetic resonance imaging (MRI) technologies [7].

Aims & Objectives
Here, we investigated the effects of long-term GHT on GMD and GMM.

Methods
20 cisgender women (CW), 11 cisgender men (CM), 20 transgender women (TW) and 10 transgender men (TM) underwent two MRI sessions, once before GHT initiation and once after 4.5 months of treatment. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Plasma levels of luteinizing hormone, follicle-stimulating hormone, progesterone, estradiol, testosterone, sex hormone binding globulin and dehydroepiandrosterone sulfate were assessed via blood draw right before or after each MRI session and added to the models as covariates.

Results
Significant time-by-group interaction effects on both GMD and GMM were found. An overlap of GMM- and GMD-specific changes was found in the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: p FWE+Bonferroni &lt;0.025). After GHT, an increase in GMD was found in the fusiform gyrus, cerebellum and lingual gyrus for TM compared to both cisgender groups. In contrast, TW showed a GMD-decrease in the rolandic operculum, insula, posterior cingulum, cerebellum and lingual gyrus when compared to CM and CW. The opposite interaction effects were found in mean diffusivity (MD; an index for GMM) of the fusiform and lingual gyrus for TM compared to both cisgender groups. An MD-increase in the insula was found for TW when compared to CM and CW.

Discussion & Conclusion
These results provide further evidence for a reliable influence of GHT on structural GM characteristics following an interregional pattern.

References
1) Cosgrove, K.P., C.M. Mazure, and J.K. Staley, Evolving knowledge of sex differences in brain structure, function, and chemistry. Biological psychiatry, 2007. 62(8): p. 847-855.
2) Lotze, M., et al., Novel findings from 2,838 adult brains on sex differences in gray matter brain volume. Scientific reports, 2019. 9(1): p. 1671.
3) Luders, E., et al., Why Sex Matters: Brain Size Independent Differences in Gray Matter Distributions between Men and Women. The Journal of Neuroscience, 2009. 29(45): p. 14265-14270.
4) Gennatas, E.D., et al., Age-related effects and sex differences in gray matter density, volume, mass, and cortical thickness from childhood to young adulthood. Journal of Neuroscience, 2017. 37(20): p. 5065-5073.
5) Koolschijn, P.C.M., J.S. Peper, and E.A. Crone, The influence of sex steroids on structural brain maturation in adolescence. PloS one, 2014. 9(1): p. e83929.
6) Witte, A.V., et al., Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain. Neuroimage, 2010. 49(2): p. 1205-1212.
7) Kranz, G.S., et al., Gender-affirming hormone treatment - A unique approach to study the effects of sex hormones on brain structure and function. Cortex, 2020. 129: p. 68-79.