Sex Differences in Human Subcortical Anatomy are Robust and Replicable in Adulthood, Already Evident Prepubertally, and Aligned with Sex Chromosomal and Gonadal Influences
- 1NIMH
Abstract
The existence and mechanistic bases of sex effects on human subcortical anatomy remain unclear. To address these gaps, we combined structural neuroimaging of sex differences in subcortical volume and shape across three independent cohorts (combined N=2,886) with neuroimaging maps of sex chromosomal and endocrine effects from three clinical cohorts (combined N=313, including sex chromosome aneuploidies and isolated gonadotropin-releasing hormone deficiency). We found that human subcortical anatomy shows focal sex differences of moderate-strong effect size during young adulthood (male-biased surface area overlying lateral/ventral putamen and pallidum, nucleus accumbens, ventral posterior complex of thalamus, anterior hippocampus, and medial and central nuclei of amygdala; female-biased surface area overlying caudate head, posterior/dorsal pallidum, mediodorsal, lateral dorsal, lateral geniculate, and medial geniculate nuclei of thalamus, posterior hippocampus, and basolateral and lateral nuclei of amygdala). These regional sex differences show strong within-sample reproducibility at modest sample sizes (N[≥]200) and are replicable in a fully independent mid-adulthood cohort. Strikingly, we find that the topography of adult subcortical sex differences is already established by pre/early puberty (age 9 years), and the same holds for cortical sex differences. Comparison with neuroimaging data from rare disorder cohorts reveals that subcortical sex differences show a statistically significant spatial and directional congruence with the anatomical effects of X-chromosome dosage in the striatum and effects of testicular hormones in the amygdala. Together, these findings provide a reference map for the fine-grained spatial patterning of sex differences in adult subcortical shape, demonstrating its replicability, establishment before pubertal progression, and spatial concordance with potentially causal sex chromosomal and gonadal effects.
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BibTeX
@misc{lee2026differences,
title = {{Sex Differences in Human Subcortical Anatomy are Robust and Replicable in Adulthood, Already Evident Prepubertally, and Aligned with Sex Chromosomal and Gonadal Influences}},
author = {H. M. Lee and S. Liu and F. Lalonde and L. Clasen and E. Guma and A. DeCasien and D. Moraczewski and A. G. Thomas and J. P. Lerch and G. A. Devenyi and M. Chakravarty and K. F. Berman and A. Delaney and A. Raznahan},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756728},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756728v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Sex Differences in Human Subcortical Anatomy are Robust and Replicable in Adulthood, Already Evident Prepubertally, and Aligned with Sex Chromosomal and Gonadal Influences
AU - H. M. Lee
AU - S. Liu
AU - F. Lalonde
AU - L. Clasen
AU - E. Guma
AU - A. DeCasien
AU - D. Moraczewski
AU - A. G. Thomas
AU - J. P. Lerch
AU - G. A. Devenyi
AU - M. Chakravarty
AU - K. F. Berman
AU - A. Delaney
AU - A. Raznahan
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756728
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756728v1
AB - The existence and mechanistic bases of sex effects on human subcortical anatomy remain unclear. To address these gaps, we combined structural neuroimaging of sex differences in subcortical volume and shape across three independent cohorts (combined N=2,886) with neuroimaging maps of sex chromosomal and endocrine effects from three clinical cohorts (combined N=313, including sex chromosome aneuploidies and isolated gonadotropin-releasing hormone deficiency). We found that human subcortical anatomy shows focal sex differences of moderate-strong effect size during young adulthood (male-biased surface area overlying lateral/ventral putamen and pallidum, nucleus accumbens, ventral posterior complex of thalamus, anterior hippocampus, and medial and central nuclei of amygdala; female-biased surface area overlying caudate head, posterior/dorsal pallidum, mediodorsal, lateral dorsal, lateral geniculate, and medial geniculate nuclei of thalamus, posterior hippocampus, and basolateral and lateral nuclei of amygdala). These regional sex differences show strong within-sample reproducibility at modest sample sizes (N[≥]200) and are replicable in a fully independent mid-adulthood cohort. Strikingly, we find that the topography of adult subcortical sex differences is already established by pre/early puberty (age 9 years), and the same holds for cortical sex differences. Comparison with neuroimaging data from rare disorder cohorts reveals that subcortical sex differences show a statistically significant spatial and directional congruence with the anatomical effects of X-chromosome dosage in the striatum and effects of testicular hormones in the amygdala. Together, these findings provide a reference map for the fine-grained spatial patterning of sex differences in adult subcortical shape, demonstrating its replicability, establishment before pubertal progression, and spatial concordance with potentially causal sex chromosomal and gonadal effects.
ER -