Effects of gender-affirming hormone therapy on gray matter density, microstructure and monoamine oxidase A levels in transgender subjects

Alterations in gray matter (GM) and monoamine oxidase A (MAO-A) distribution across the brain have been found in various neuropsychiatric conditions. MAO-A catalyzes the oxidative degradation of various monoamines and is thus implicated in neuroplastic processes that influence GM density (GMD) and microstructure (GMM) of the brain. Sex-specific differences in these patterns are well documented, however studying the long-term effects of certain sex steroids on the brain are limited due to hormonal fluctuations under naturalistic conditions. Due to the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy represent a valuable cohort to investigate such changes of GM and concomitant MAO-A density. Here, we investigated the effects of long-term gender-affirming hormone therapy over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men were recruited. All participants underwent two MRI scans in a longitudinal design. PET scans using [11C]harmine were performed before each MRI session in a subset of 35 individuals. Between baseline and follow-up imaging, transgender subjects underwent gender-affirming hormone therapy. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: pFWE+Bonferroni < 0.025). In terms of MAO-A distribution volume, no significant effects were found. The present results are indicative of a reliable influence of gender-affirming hormone therapy on GMD and GMM following an interregional pattern. Nevertheless, future studies with larger sample sizes are needed to further investigate the relationship between sex steroids, gray matter alterations and MAO-A density. ### Competing Interest Statement With relevance to this work there is no conflict of interest to declare. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. G.S. Kranz declares that he received conference speaker honorarium from Roche, AOP Orphan and Pfizer. P. Handschuh received authorship honoraria from MedMedia Verlag. The other authors report no conflict of interest. ### Clinical Trial NCT02715232 ### Funding Statement This research was funded in whole, or in part, by the Austrian Science Fund (FWF) [Grant number KLI 504, PI: Rupert Lanzenberger]. M. Murgas is funded by the Austrian Science Fund (FWF) [Grant number DOC 33-B27, Supervisor R. Lanzenberger]. MB. Reed and M. Kloebl are recipients of a DOC fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. This project was performed with the support of the Medical Imaging Cluster of the Medical University of Vienna, and by the grant Interdisciplinary translational brain research cluster (ITHC) with highfield MR from the Federal Ministry of Science, Research and Economy (BMWFW), Austria. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee of the Medical University of Vienna gave ethical approval for this work. (EC number 1104/2015). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger{at}meduniwien.ac.at with any questions or requests.