BACKGROUND
Menopause is associated with increased cardiovascular and cerebrovascular disease risk, partly attributed to declines in oestrogen and its effects on endothelial function and arterial stiffness. Whether menopausal stage independently affects vascular function beyond chronological ageing remains unclear, particularly for the cerebrovasculature.
METHODS
Thirty-nine healthy, non-smoking females aged 40–65 years were recruited and classified by STRAW+10 criteria into premenopausal (PRE, n=10; 0 ± 0 years since FMP), early postmenopausal (E-POST, n=15; 3 ± 1 years since FMP), and late postmenopausal (L-POST, n=14; 11 ± 4 years since FMP). Premenopausal females were tested in the luteal phase. All but three participants (one per group) met Australian physical activity guidelines. After fasting and abstaining from caffeine, alcohol, nitrate-rich foods, and vigorous exercise, participants underwent assessment of resting blood pressure, arterial stiffness (PWV, augmentation index, AIx75), brachial artery flow-mediated dilatation, and cerebrovascular reactivity (CVR) to 5% CO2 hypercapnia in the middle cerebral artery (MCAv, intracranial) and internal carotid artery (ICA, extracranial). Plasma was analyzed for nitrate, nitrite, estradiol, FSH, and progesterone. Group differences were assessed by one-way ANOVA, with age and estradiol evaluated as covariates via ANCOVA, and associations tested by Pearson correlation.
KEY RESULTS
Estradiol differed markedly across groups (PRE 154.1 [117.8–194.1] vs E-POST 6.6 [5.1–8.1] vs L-POST 0 [0–8.0] pg/ml; P<0.001), as did FSH and progesterone. There were no group differences in resting SBP (P=0.505), DBP (P=0.371), MAP (P=0.382), central SBP (P=0.258), PWV (6.4 ± 2.7 vs 6.8 ± 2.8 vs 8.6 ± 3.0 cm/s; P=0.129), AIx (P=0.227), or brachial FMD (7.0 ± 3.7% vs 6.1 ± 3.5% vs 5.9 ± 3.2%; P=0.696). MCAv increased 33–40% from baseline with hypercapnia in all groups, with no between-group differences in MCAv CVR (P=0.442) or other intracranial indices. The absolute change in ICA blood flow was lower in PRE versus E-POST and L-POST (2.3 ± 1.5 vs 4.8 ± 2.4 vs 4.9 ± 1.6 ml/s; P=0.013), and the relative change was lower in PRE versus L-POST (26.5 ± 19.2% vs 47.8 ± 12.6%; P=0.010), but these differences were abolished after adjustment for age or estradiol. ICA CVR did not correlate with age (r=0.264, P=0.145). Plasma nitrite (P=0.128) and nitrate (P=0.465) did not differ between groups. There were no significant associations between estradiol and FMD (r=-0.106, P=0.590), estradiol and ICA CVR (r=-0.085, P=0.708), or estradiol and NO metabolites (nitrate r=-0.156, P=0.468; nitrite r=-0.118, P=0.468), although in postmenopausal-only log-transformed analyses FSH correlated with FMD (r=-0.592, P=0.006) and estradiol correlated with ICA CVR (r=0.667, P=0.035). The late postmenopausal group had the highest self-reported physical activity (2573 ± 1586 MET min/week).
CLINICAL IMPLICATIONS
In healthy, physically active females across the early and late postmenopausal years, peripheral vascular function (FMD, arterial stiffness) and cerebrovascular reactivity appear largely preserved, and reproductive hormone levels or NO bioavailability are not directly associated with these measures. The single between-group difference in extracranial (ICA) reactivity was attributable to age rather than menopausal status, underscoring the difficulty of separating ageing from menopause. The high physical activity of the cohort, particularly in L-POST, may have conferred protective effects and could explain the divergence from prior studies that found reduced vascular and cerebrovascular function in postmenopausal females with lower fitness. These findings support maintaining physical activity throughout the menopausal transition as a potential strategy to preserve vascular and cerebrovascular health, although adequately powered longitudinal studies are needed to confirm causality and dissect the contributions of oestrogen decline, ageing, and fitness.