Sex Hormone Manipulation in Humans: Are Cerebral Blood Flow Impacts Sex and Region Specific?

Background: Females typically display higher cerebral blood flow (CBF) than males at global and regional levels. Greater CBF in females may be due to sex or sex hormone influences in the cerebral vasculature, but human studies indicate estrogen is only weakly correlated with CBF; possibly due to complexity of endogenous sex hormones. The present study design was aimed at minimizing sex hormone influence on CBF via gonadal axis hormone suppression (HS), then testing fundamental impact of primary sex hormones on CBF by single-hormone add-back (SHAB; Estradiol only in females and testosterone only in males). We hypothesized that 1) In females CBF would decrease during HS, but SHAB would restore CBF to baseline levels and 2) In males CBF would decrease during HS and SHAB would continue to decrease CBF. Methods: 13 healthy subjects (24±4 years, 8 F) underwent arterial spin labeling MRI to assess global and regional CBF at three different time points: baseline (BL), hormone suppression (HS), and single-hormone add-back (SHAB). Women completed BL MRI scans on menstrual cycle days 1-7. For HS, subjects took an oral gonadotropin-releasing hormone (GnRH) antagonist (Orilissa) and an aromatase inhibitor (Anastrozole; males only) for 5-6 days. For SHAB, subjects continued Orilissa and began taking sex specific hormone of estradiol (females) and testosterone (males,+Anastrozole) for 4-5 days prior to the SHAB MRI scan. CBF in Grey Matter (GM), White Matter (WM), brain stem and cerebellum, subcortical regions, and frontal, temporal, parietal, and occipital lobes were assessed. One-way ANOVA assessed differences between conditions. Results: Females displayed no change in CBF in GM (p=0.87), WM (p=0.44), or any brain lobe (p all >0.44) in between BL, HS, and SHAB. In males CBF was decreased in the occipital lobe from BL to HS (p=0.038) and BL to SHAB (p=0.007). Males displayed a decrease in GM CBF from BL to SHAB (p=0.05), but no change between BL and HS (p=0.21). In males WM decreased from BL to HS (p=0.048) and BL to SHAB (p=0.001), with a trend for lower CBF in SHAB compared to HS (p=0.058). Males exhibited decreased CBF in the parietal lobe from BL to SHAB (p=0.025), but not BL to HS (p=0.13). Males showed a trend for decreased CBF in the frontal lobe (p=0.082), but displayed no change in CBF between conditions for the brainstem and cerebellum (p all > 0.12), subcortical regions, nor temporal lobe. Serum samples are currently being analyzed for sex hormones to verify Orilissa efficacy. Conclusion: In support of our hypothesis, during HS males displayed decreased CBF in WM and occipital lobe. With testosterone restoration, males continued to decrease CBF in GM, WM, and parietal and occipital lobes. In contrast, females did not demonstrate a change in CBF in GM or WM under HS or SHAB. The lack of change in females could be due to a) short duration of the GnRH antagonist b) balanced vascular effect of hormone changes (e.g. loss of estrogen dilation and loss of testosterone/progesterone constriction) or c) sex differences in CBF are due to sex steroid independent mechanisms. Future work will need to sustain HS and/or SHAB for longer durations to better mimic clinical conditions. NIH R01 HL150361 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.