The influence of sex hormones and sex chromosomes on the sexual differentiation of human brain structure: analysis of regional gray matter in women with complete androgen insensitivity syndrome

Event Abstract Back to Event The influence of sex hormones and sex chromosomes on the sexual differentiation of human brain structure: analysis of regional gray matter in women with complete androgen insensitivity syndrome Marine Manard1*, Sonia Ouerdi1, Judy Van Hemmen2 and Julie Bakker1 1 University of Liège, GIGA-Neurosciences: Neuroendocrinology unit, Belgium 2 VU University Medical Center, Department of Medical Psychology, Netherlands Introduction. Sex differences in brain structure and their underlying mechanisms are still under examination. Even though the literature leads to divergent results, both global and regional structural sex differences have been suggested. While men tend to show larger global brain volume than women (Goldstein et al., 2001; Gur et al., 2016), regional differences appear according to the used methodology. For example, greater gray matter volume was found at the cortical level in women but at the subcortical level and for white matter in men (Hoekzema et al., 2015). Moreover, the underlying mechanisms of sex differentiation in the brain also remain under debate. Indeed, these structural sex differences are suggested to be sensitive to a complex interplay between sex chromosome genes, sex hormones, and the environment (Savic et al., 2017). The Complete Androgen Insensitivity Syndrome (CAIS) provides a unique model to assess the influence of sex hormones and sex chromosome genes on brain sexual differentiation. CAIS is a disorder of sex development involving a normal amount of sex chromosomes (46,XY karyotype) but no response to testosterone due to X-chromosomal genetic mutations leading to nonfunctional androgen receptors. As a result, these individuals are phenotypically female despite having normal to high levels of testosterone (Oakes et al., 2008). In addition, they show female-typical behavior in terms of gender role or gender identity (Hines et al., 2003), as well as female-typical neural activation in response to emotional (Hamann, et al., 2014) and mental rotation tasks (Van Hemmen et al., 2016). These results suggest that gonadal hormone exposure and/or female-typical socialization might probably account for sex differences in the brain. However, a potential role for sex chromosome genes cannot be excluded in the sexual differentiation of the human brain; therefore, in the present study we evaluated regional gray matter volumes in women with CAIS. Methods. Voxel-Based Morphometry analyses (SPM12) were conducted using high-resolution T1-weighted anatomical images obtained from 21 women diagnosed with CAIS, 31 control men, 33 control women taking hormonal contraceptives and 33 control women with regular menstrual cycles. Images were segmented, modulated, normalized using a study-specific Dartel template and smoothed with an 8 mm FWHM Gaussian kernel. A full factorial analysis was then used to assess whole-brain potential differences in gray matter volumes between the groups and accounting for total intracranial volume. Results. Sex differences were observed with control women showing greater gray matter volumes in the parietal gyrus, olfactory gyrus, middle temporal pole, frontal areas, thalamus, hippocampus and cingulate regions compared to control men. Furthermore, women with CAIS had greater gray matter volumes in the precuneus, superior medial frontal gyrus, supplementary motor area, parietal lobule, and olfactory gyrus compared to control men. All other contrasts (CAIS vs control women, control women vs control men, control men vs CAIS) did not show any significant differences at p<0.05 FWE. Discussion. As observed in several other studies, control women showed greater gray matter volumes than control men in various brain areas (Goldstein et al. 2001; Good et al., 2001; Hoekzema et al., 2015; Luders et al. 2009). Interestingly, the distribution of the regional differences observed between control men and control women with or without hormonal contraceptives, respectively, seems to differ. This regional difference might be related to the hormonal contraception intake (Pletzer et al., 2010), although no difference was found between the two groups of control women. Regardless of minor regional differences, women with CAIS also showed greater gray matter volumes than control men in several cortical areas, whereas they did not differ from control women. This result is in accordance with the assumption that women with CAIS tend to show a female-typical phenotype, including regional gray matter volumes. Given the androgen resistance observed in women with CAIS, these results suggest a key role of androgens in the sexual differentiation of gray matter. Indeed, the differences observed between women with CAIS and control men are likely not due to chromosomal differences, but rather reflects an interplay between hormonal mechanisms and environmental factors since female-typical socialization cannot be ruled out given that women with CAIS were reared as girls. Acknowledgements This study was supported by a VICI grant from the Dutch Science Foundation (Nederlandse Organisatie voor Wetenschappelijk onderzoek, NWO, 453-08-003. References Goldstein, J. M., Seidman, L. J., Horion, N. J., Makris, N., Kennedy, D. N., Caviness, V. S., Faraone, S. V. & Tsuang, M. T. (2001). Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cerebral Cortex, 11, 490-497. Gur, R. E., & Gur, R. C. (2016). Sex differences in brain and behavior in adolescence: Findings from the Philadelphia Neurodevelopmental Cohort. Neuroscience and Biobehavioral Reviews, 70, 159-170. Hoekzema, E., Schagen, S. E., Kreukels, B. P., Veltman, D. J., Cohen-Kettenis, P. T., Delemarre-van de Waal, H., & Bakker, J. (2015). Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain. Psychoneuroendocrinology, 55, 59-71. Savic, I., Frisen, L., Manzouri, A., Nordenstrom, A., Hirschberg, A. L. (2017). Role of Testosterone and Y Chromosome Genes for the Masculinization of the Human Brain. Human Brain Mapping, 38, 1801-1814. Oakes, M. B., Eyvazzadeh, A.D., Quint, E., Smith, Y.R. (2008). Complete androgen insensitivity syndrome—a review. Journal of Pediatric & Adolescent Gynecology, 21, 305–310. Hamann, et al., 2014 Van Hemmen, J., Veltmann, D. J.? Hoekzema, E., Cohen-Kettenis, P. T., Dessens, A. B., Bakker, J. (2016). Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes. Cerebral Cortex, 26(3), 1036-1045. Good, C.D., Johnsrude, I., Ashburner, J., Henson, R.N., Friston,K.J., Frackowiak, R.S. (2001). Cerebral asymmetry and theeffects of sex and handedness on brain structure: a voxel-basedmorphometric analysis of 465 normal adult human brains. NeuroImage, 14, 685—700. Luders, E., Gaser, C., Narr, K.L., Toga, A.W., (2009). Why sexmatters: brain size independent differences in gray mat-ter distributions between men and women. Journal of Neuroscience, 29, 14265—14270. Pletzer, B., Kronbichler, M., Aichhorn, M., Bergmann, J., Ladurner, G., Kerschbaum, H.H., (2010). Menstrual cycle and hormonal contraceptive use modulate human brain structure. Brain Research. 1348, 55–62. Keywords: Sex Differentiation, complete androgen insensitivity syndrome, voxel-based morphometry, brain structure, sex hormones Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Oral Presentation Topic: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homeostatic Challenge Citation: Manard M, Ouerdi S, Van Hemmen J and Bakker J (2019). The influence of sex hormones and sex chromosomes on the sexual differentiation of human brain structure: analysis of regional gray matter in women with complete androgen insensitivity syndrome. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00046 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Miss. Marine Manard, University of Liège, GIGA-Neurosciences: Neuroendocrinology unit, Liège, Liège, 4000, Belgium, marine.manard@ulg.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. 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