THE RELATIONSHIP OF BRAIN NEUROTRANSMITTER LEVELS AND SEX HORMONES

Abstract Introduction Several studies aimed to deepen our understanding of the relationship between sex hormones and neurotransmitter levels. While, mainly sex differences in neurotransmitter concentrations could be revealed, one study reported an influence of sex hormones during the menstrual cycle on cortical GABA levels in women [1], but did not investigate subcortical regions. In a previous study, we were able to demonstrate effects of gender-affirming hormone therapy in female-to-male transgender study participants on hippocampal GABA levels [2]. Aims & Objectives Here, we aimed to further investigate the relationship of the sex hormones estrogen and testosterone and the main cerebral inhibitory and excitatory neurotransmitter GABA and glutamate, respectively. Beside the previous reported effects of hormonal treatment on hippocampal GABA levels, the relationship of sex hormones will be tested in a mixed (female and male) cohort and within a male and female subgroup, respectively. Moreover, we extended our investigation on the insula, putamen, pallidum and thalamus in an exploratory approach. Methods To this end, GABA and glutamate levels were quantified in a study cohort including 36 healthy subjects (12 males, mean± SD: 25±7 years) using magnetic resonance spectroscopy imaging (MRSI). All participants underwent a MRSI measurements, using a 3D GABA-edited MEGA-LASER sequence (TE=68ms, TR=1.6s, volume of interest: 80(l-r)×90(a-p)×80(s-i) mm3 and a field of view: 160×160×160 mm3, with a matrix size of 16×16×16 matrix (~1cm3 nominal voxel size) [3]). MRSI measurements were conducted on a 3T MR Prisma systems (Siemens, Erlangen, Germany) using LCModel and Matlab for data analysis. The GABA+/tCr and the Glx/tCr ratio (GABA+ = GABA+macromolecules; tCr = total creatine; Glx = glutamate+glutamine) were quantified in the hippocampus, insula, putamen, pallidum and thalamus in a region-of-interest-based (ROI) approach as described in [4]. Plasma levels of estradiol (pg/ml) and testosterone (ng/ml) were quantified. Statistical analyses were performed using two-sided Spearman correlation in SPSS (IBM SPSS statistics v25). Results Correlation analyses revealed no significant interactions between sex hormones and hippocampal GABA+/tCr or Glx/tCr in the whole and female or male subgroup, respectively. However, a significant but weak correlation between Glx/tCr and estradiol levels in the putamen in the whole group (p=0.039, r= 0.35), uncorrected for multiple comparison, was revealed. Discussion & Conclusion While the hippocampus is capable of local hormone production [5], no significant relationship to sex hormone concentration in peripheral plasma could be shown. Nevertheless, we observed a correlation between the glutamatergic system in the putamen and estradiol levels which was reported to have a modulatory role in neurotransmitter systems and was shown to be enlarged in transgender women [6]. However, our results have to be interpreted with caution due the missing correction for multiple testing. References [1]Epperson C N, Haga K, Mason G F, Sellers E, Gueorguieva R, Zhang W, Weiss E, Rothman D L, and Krystal J H, Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry, 2002;59:851-8, yoa10025 [2]Spurny-Dworak B, Handschuh P, Spies M, Kaufmann U, Seiger R, Klobl M, Konadu M E, Reed M B, Ritter V, Baldinger-Melich P, Bogner W, Kranz G S, and Lanzenberger R, Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort. Psychoneuroendocrinology, 2022;138:105683, 10.1016/j.psyneuen.2022.105683 [3]Bogner W, Gagoski B, Hess A T, Bhat H, Tisdall M D, van der Kouwe A J, Strasser B, Marjanska M, Trattnig S, Grant E, Rosen B, and Andronesi O C, 3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI. Neuroimage, 2014;103:290-302, 10.1016/j.neuroimage.2014.09.032 [4]Spurny B, Heckova E, Seiger R, Moser P, Klobl M, Vanicek T, Spies M, Bogner W, and Lanzenberger R, Automated ROI-Based Labeling for Multi-Voxel Magnetic Resonance Spectroscopy Data Using FreeSurfer. Front Mol Neurosci, 2019;12:28, 10.3389/fnmol.2019.00028 [5]Hojo Y, Higo S, Kawato S, Hatanaka Y, Ooishi Y, Murakami G, Ishii H, Komatsuzaki Y, Ogiue-Ikeda M, Mukai H, and Kimoto T, Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Front Endocrinol (Lausanne), 2011;2:43, 10.3389/fendo.2011.00043 [6]Luders E, Sanchez F J, Gaser C, Toga A W, Narr K L, Hamilton L S, and Vilain E, Regional gray matter variation in male-to-female transsexualism. Neuroimage, 2009;46:904-7, 10.1016/j.neuroimage.2009.03.048