Physiology · May 2026
Short-term sex hormone suppression increases cerebrovascular reactivity in females: regional influence of blood pressure and cyclooxygenase
By Heenan LJ, Dider K, Ortiz A et al.
Background: Cerebrovascular reactivity (CVR)—the increase in cerebral blood flow (CBF) in response to hypercapnia—reflects intracranial vascular health, with lower CVR linked to cerebrovascular disease progression. Importantly, greater declines in CVR are observed post-menopause beyond what is expected due to age, indicative of a potential hormonal influence on CVR in females. However, data on the influence of hormones across the menstrual cycle remain equivocal. Sex hormones may regulate CVR via the cyclooxygenase (COX) pathway, which produces dilatory prostaglandins to increase CBF in response to hypercapnia. Interestingly, sex steroids can modify COX expression and function in a potentially regionally heterogeneous manner. We aimed to assess the influence of sex hormones on CVR using a gonadotropin releasing hormone antagonist (GnRHa), which acutely suppresses sex hormone production and reduces peripheral vascular function in young, healthy females. We hypothesized short-term GnRHa would result in decreased CVR due to lower COX-mediated dilation. Methods: CVR was measured in 11 young, healthy females (21 ± 4 yr, 22 ± 2 kg/m 2 ) using magnetic resonance imaging (3T; pseudo-continuous arterial spin labeling) to quantify CBF at room air and during hypercapnia (+8 mmHg end-tidal CO 2 ; PETCO 2 ). Using a randomized, double-blind, placebo-controlled design, two baseline scans were performed: one after a placebo condition and one following administration of indomethacin, a non-selective COX inhibitor (INDO; ~1.5 mg/kg). These visits were repeated after ≥ 4 days of GnRHa (elagolix; 200mg 2x/day). Mean arterial pressure (MAP) was measured during each room air and hypercapnia scan to calculate cerebrovascular conductance (CVC = CBF/MAP). CVR was calculated at the whole brain, grey matter (GM), white matter (WM) and lobular level as a change in CBF (CVRCBF = %ΔCBF/ΔPETCO 2 ; %/mmHg) or CVC (CVRCVC = %ΔCVC/ΔPETCO 2 ; %/mmHg) to account for changes in MAP. Data were analyzed using two-way repeated measures ANOVA, presented as mean ± SD. Results: GnRHa (5 ± 1 days) reduced serum estradiol, progesterone, and testosterone (p < 0.05) but did not alter basal CBF or CVC at the whole brain or lobular level (p ≥ 0.33). Surprisingly, whole brain CVRCBF increased after GnRHa (4.9 ± 2.3 vs 6.6 ± 3.2 %/mmHg, p = 0.047) due to elevated GM (p = 0.02), but not WM reactivity (p = 0.39). At the lobular level, GnRHa increased CVRCBF in the subcortical regions (+58 ± 81%) and temporal lobe (+76 ± 95%; p ≤ 0.03) while frontal lobe CVR appeared to elevate (p = 0.07). Interestingly, MAP responses to hypercapnia were slightly greater after GnRHa (+5 ± 3 mmHg) relative to baseline (+3 ± 5 mmHg, p < 0.05). Expressing data as CVRCVC abolished differences in CVR in the whole brain, GM, and subcortical regions, but the temporal lobe remained elevated (p = 0.02). INDO decreased CVRCBF and CVRCVC at baseline in all lobes (all p ≤ 0.04) except the parietal lobe. After GnRHa, INDO reduced CVR in all lobes (all p ≤ 0.03). A trend was observed towards a condition–by–drug interaction in the temporal lobe (p = 0.07) such that INDO decreased CVR more after GnRHa (-48 ± 40%) relative to baseline (-35 ± 51%). Discussion: Contrary to our hypothesis, short-term GnRHa did not impair CVR and instead augmented reactivity in a lobe-specific manner. While some of these lobes (subcortical and frontal lobes) were due to greater chemoreflex-mediated MAP responses, temporal lobe CVR remained elevated, suggesting that intracranial vascular reactivity was acutely elevated by GnRHa. However, this elevation may not be explained by an increase in COX signaling. Future studies should identify additional mechanisms by which GnRHa enhances CVR. This abstract was presented at the American Physiology Summit 2026 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.