Cyclic fluctuations in hypothalamic–pituitary–gonadal axis (HPG‐axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T₁‐weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid‐luteal) to investigate whether HPG‐axis hormone concentrations co‐fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17β‐estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (μFA; 17β‐estradiol: β₁ = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: β₁ = 0.111, HDI = [0.157, 0.364]), while follicle‐stimulating hormone (FSH) was directly proportional to CT (β₁ = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (D_iso) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (β₁ = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; β₁ = −0.749, HDI = [−11.604, −0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain‐wide changes in human WM microstructure and CT coinciding with menstrual cycle‐driven hormone rhythms. Effects were observed in both classically known HPG‐axis receptor‐dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG‐axis hormone fluctuations may have significant structural impacts across the entire brain.

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