THE ROLE OF ENDOGENOUS SEX HORMONES ON CEREBROVASCULAR REACTIVITY IN PREMENOPAUSAL FEMALES

Abstract

Background: Cerebrovascular reactivity (CVR) is a measure of cerebrovascular function that utilizes elevations in arterial carbon dioxide (CO2) to increase cerebral blood flow (CBF). Reduced CVR is associated with cerebrovascular risk, such as stroke and cognitive decline. CVR is a response due, in part, to the direct effects of CO2, systemic blood pressure responses, and the activation of enzymes that dilate intracranial vessels, such as cyclooxygenase (COX). There is evidence of hormonal regulation of CVR in females, with parallel declines in CVR and elevated cerebrovascular risk occurring after menopause. Interestingly, there is evidence of hormonal regulation of COX expression and function, indicating that the role of hormones on CVR may be via alterations in COX signaling. Gonadotropin releasing hormone antagonists (GnRHa) are a class of drugs that can acutely decrease sex steroid concentrations in young, healthy females and are therefore a useful tool in determining the influence of sex hormones on vascular function. Therefore, we hypothesized that GnRHa would reduce CVR at global and lobular levels and that these reductions in CVR would be partially explained by a loss of COX signaling. Methods: CVR was measured in 11 young, healthy females (21 ± 4 yrs, BMI 22 ± 2 kg/m2) using magnetic resonance imaging (3T; pseudo-continuous arterial spin labeling) to quantify CBF at rest and during isooxic hypercapnia (+8 mmHg end-tidal CO2; PETCO2). In this randomized, double-blind, placebo-controlled trial, two baseline trials were performed, once after a placebo and once after administration of the non- selective COX inhibitor indomethacin (~1.5 mg/kg). These visits were repeated after ≥ 4 days of GnRHa (elagolix; 200 mg twice daily). CVR was calculated as the %ΔCBF/ΔPETCO2 (CVRCBF; %/mmHg) at the whole brain, grey matter (GM), white matter (WM), and lobular perfusion levels. Additionally, to account for potential differences in mean arterial pressure (MAP) responses to GnRHa, CVR was also calculated as a change in cerebrovascular conductance (CVC; CBF/MAP) as %ΔCVC/ΔPETCO2 (CVRCVC; %/mmHg). Data are presented as mean ± standard deviation. Results: After an average of 5 ± 1 days on GnRHa, significant reductions in serum estradiol, progesterone, and testosterone concentrations as well as increased sex-

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hormone binding-globulin were observed (p < 0.05). Resting CBF was unchanged at the whole brain,

GM, WM, and lobular level (all p ≥ 0.33). However, CVRCBF increased in the whole brain (4.9 ± 2.3 vs 6.6 ± 3.2 %/mmHg, p = 0.047) and GM (5.0 ± 2.1 vs 7.1 ± 3.3 %/mmHg, p = 0.022), but not WM (p = 0.4) following GnRHa. Heterogeneity was observed at the lobular level such that CVR was elevated in the subcortical regions, frontal lobe, and temporal lobe following GnRHa (all p ≤ 0.023) while no significant changes were detected in the brainstem and cerebellum, parietal lobe, or occipital lobe (p ≥ 0.14). After correction for multiple comparisons, CVRCBF remained significantly elevated in the subcortical regions and temporal lobe. However, when assessing CVRCVC, no elevations in reactivity were observed in the whole brain, GM, WM, or any lobe with exception for the temporal lobe, which increased after GnRHa (p = 0.024). This discrepancy between CVRCBF and CVRCVC appears to be due to an augmented pressor response to hypercapnia after GnRHa, resulting in greater MAP responses than at baseline. While indomethacin robustly decreased CVRCBF and CVRCVC at the whole brain, GM, and lobular perfusion levels (all p ≤ 0.027), there was no GnRHa–by–indomethacin interaction effect, with only a trend observed in a greater COX component in temporal lobe CVRCBF (p = 0.072). Conclusions: Contrary to our hypothesis, elevations in CVR were demonstrated after GnRHa in a region-specific manner. These appear largely attributable to a change in systemic hemodynamic control of MAP, indicated by the elevated reactivity observed in CVRCBF being abolished after accounting for MAP responses using CVRCVC. However, the elevation in temporal lobe CVRCVC provides evidence for a local enhancement in dilatory responsiveness, but these effects are not explained by an increase in COX signaling. Future studies are required to understand the clinical relevance and mechanistic underpinning of these region-specific elevations in CVR.