Fluctuations in gonadal hormones, particularly progesterone and estradiol, regulate the menstrual cycle and affect brain structure, behavior, and function. These hormones exert their effects via widely distributed brain receptors. However, several cross-sectional studies comparing menstrual phases have revealed regional gray matter variations but fail to capture individual hormonal rhythms. Recent longitudinal neuroimaging research approaches offer higher sensitivity by tracking within-person hormone-brain dynamics over time.
A recent study published in Nature Neuroscience examined how daily fluctuations in estradiol and progesterone influence the structure of the brain across the menstrual cycle. A total of 5 participants were included in this study. Three healthy females with typical (age = 37 years), oral contraceptives (mean age = 31 years), and the public 28andMe dataset (mean age = 23 years), whereas one female with endometriosis (mean age = 30 years) participated while freely cycling. A healthy male (age 36) served as the fifth participant and comparison. No participants reported historical substance-related, psychiatric, or neurological disorders.
All five participants underwent dense-sampling neuroimaging across five weeks of weekday testing, resulting in a total of 25 MRI sessions each, except for one, which had 30 sessions. All scans were acquired on a 3T Siemens Prisma using standardized T1-weighted parameters.
Results showed that typical and 28andMe cycles showed balanced follicular-luteal patterns, whereas endometriosis exhibited shorter cycles with estradiol patterns. Oral contraceptives suppressed progesterone while maintaining estradiol patterns. Multivariate analysis revealed significant hormonal differences across groups (P < 0.001). Post-hoc t-test demonstrated that elevated estradiol levels were observed significantly in endometriosis compared to the 28andMe (P = 0.002) and reduced progesterone in oral contraceptive users compared to typical (P = 0.005) and 28andMe (P = 0.003) females.
Generalized additive models (GAMS) and time-series regression analysis revealed that whole brain volumetric spatiotemporal pattern 1 (VSTP1; variance = 47.7%), VSTP2 (20.4%), and VSTP3 (9.7%) fluctuated with hormones; progesterone and estradiol-to-progesterone ratios correlated with VSTP1 and VSTP2, especially in typical and 28andMe cycle. Estradiol was significantly associated with VSTP1 in endometriosis (β = 0.006, PFDR = 0.010) and oral contraceptive (β = 0.006, PFDR = 0.023) cycles. Cortical thickness spatiotemporal pattern 2 (CSTP2) showed significant hormonal associations with progesterone (β = 0.042, PFDR < 0.001) and estradiol-to-progesterone ratio (β = 0.023, PFDR < 0.001) in the 28andMe cycle.
Vertex- and voxel-wise analyses confirmed that singular value decomposition (SVD) findings showed hormone-related brain volume changes. Estradiol effects were prominent in endometriosis and oral contraceptive cycles, whereas progesterone effects were in typical cycles. Significant positive correlations were noted between the ratio of estradiol-to-progesterone and cortical thickness of the lateral occipital gyrus, as well as the parahippocampal gyrus, among all participants.
The fifth participant showed low estradiol (128.7±17.3 pmol l−1) and progesterone levels (0.863±0.582 nmol l−1) after five weeks. VSTP analysis demonstrated structural variance of 58% in VSTP1, 19.3% in VSTP2, and 12.9% in VSTP3. Similarly, CSTP analysis reported that the variance of 40.2% in CSTP1, 14.2% in CSTP2, and 11.3% in CSTP3. Overall, no significant associations with hormones were observed. Voxel- and vertex-wise analyses similarly showed no significant correlation with hormone levels.
The study’s limitations include small, dense-sampling samples, variations in scanning schedules, participant factors, and hormone assay methods. This study highlights that hormone and brain associations are highly individualized and depend on the hormonal context, such as typical estradiol and progesterone cycles, and elevated estradiol in endometriosis. By identifying dynamics within person fluctuations, these findings revealed how hormonal milieus shape brain structure, underscoring the value of personalized approaches in studying brain plasticity.
Reference: Heller C, Güllmar D, Colic L, et al. Hormonal milieu influences whole-brain structural dynamics across the menstrual cycle using dense sampling in multiple individuals. Nat Neurosci. 2025. doi:10.1038/s41593-025-02066-2
