Does the suppression of endogenous sex hormones change cerebrovascular reactivity in a sex- and region-specific manner?

Background: Cerebrovascular reactivity (CVR) to elevated arterial carbon dioxide (CO2) content is a measure of vessel dilatory responsiveness. Lower CVR is linked to cognitive decline, Alzheimer’s disease risk, and mortality. Data on sex differences in CVR are conflicting and the role of sex hormones in CVR remain unclear. Animal data suggests that chronic elevations in estrogen enhances cerebrovascular dilation while the opposite is observed with chronic testosterone exposure. Limited human data demonstrates regional degradations in CVR with age coinciding with lower sex steroid concentrations. This study investigated CVR in a sex- and region-specific manner using endogenous sex hormone manipulations by measuring cerebral blood flow (CBF) at baseline (BL), after acute gonadal axis sex hormone suppression (HS), and after the addition of a single sex hormone (single-hormone add-back; SHAB). We hypothesized 1) BL CVR will be higher in females, 2) HS will increase CVR in males and decrease in females, and 3) SHAB will restore or magnify sex differences observed at BL. Methods: CVR was measured in 12 healthy, unmedicated, disease-free participants (8F, 23±4 yrs) using arterial spin labeling MRI to quantify CBF while inspiring room air and hypercapnic gas at +8 mmHg end-tidal CO2 (PETCO2). This was repeated for BL, HS, and SHAB conditions. HS was achieved by 5-6 days of gonadotropin-releasing hormone antagonism (Orilissa) and aromatase inhibition (Anastrozole; males only). SHAB was achieved by continued Orilissa (and Anastrozole) with the addition of estradiol (females) or testosterone (males) for 4-5 days. Females were studied on days 1-7 of the menstrual cycle for BL scans and did not use hormonal contraceptives. CBF was measured in both white matter (WM) and six gray matter (GM) subregions (i.e. brain stem, subcortical regions, and frontal, parietal, occipital, and temporal lobes). CVR was calculated as %ΔCBF/ΔPETCO2 (%/mmHg). Results: In WM, no effect of sex or hormonal condition on CVR was found (BL: 5.1±2.4Males vs. 5.0±2.8Females; HS: 5.8±2.4M vs. 5.8±2.7F; SHAB: 5.6±0.4M vs. 5.3±2.3F %/mmHg). In GM, no differences were observed in the brain stem, subcortical regions, or occipital lobe. However, temporal lobe CVR increased in females from BL to HS (4.2±2.2 vs. 6.1±2.4 %/mmHg; p=0.043). Additionally, females demonstrated trends towards increased CVR from BL to SHAB in the frontal (4.1±1.7 vs. 5.5±2.6 %/mmHg; p=0.072) and parietal lobes (4.9±2.1 vs.6.4±2.4 %/mmHg; p=0.088). HS and SHAB increased resting MAP in males only, but did not affect the magnitude of MAP responses to hypercapnia. Sex steroid samples are currently being tested to assess the efficacy of HS and SHAB interventions. Conclusions: Contrary to our hypothesis, no sex differences in BL CVR were observed in GM or WM. Additionally, HS and SHAB increased–as opposed to decreased–CVR in females in frontal, parietal, and temporal lobes. These data suggest that HS may enhance cerebrovascular dilation in females only, an effect that should be investigated with longer HS durations as well as assessment of other hormone additions (e.g. progesterone, DHEA). Funding 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.