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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Elevated plasma homocysteine and cysteine are associated with endothelial dysfunction across menopausal stages in
Amy C Keller1,2, Jelena Klawitter3, Kerry L Hildreth4
1Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, Colorado.
Insights
Declining estradiol during menopause increases homocysteine (Hcy) and cysteine, contributing to endothelial dysfunction. Nutritional support targeting Hcy metabolism may improve vascular health in women.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Nutritional Science
Background:
- Hyperhomocysteinemia (Hcy) is linked to endothelial dysfunction and cardiovascular disease (CVD).
- Endothelial dysfunction is a known complication across menopause stages.
- The relationship between Hcy metabolism and endothelial function during menopause requires further investigation.
Purpose of the Study:
- To investigate the association between elevated homocysteine (Hcy) and markers of Hcy metabolism with endothelial dysfunction across different stages of the menopause transition.
- To explore the role of declining estradiol levels in Hcy metabolism and endothelial function.
- To assess the impact of dietary micronutrient intake on Hcy metabolism and endothelial function.
Main Methods:
- Healthy women (n=128, ages 22-70) were categorized by menopausal stage: premenopausal, perimenopausal (early/late), and postmenopausal (early/late).
- Measurements included brachial artery flow-mediated dilation (FMD), plasma Hcy, cysteine, methionine, and dietary intake of B vitamins (B6, B12, folate).
- Statistical analyses correlated Hcy metabolism markers, estradiol levels, FMD, and nutrient intake.
Main Results:
- Hcy and cysteine concentrations increased, while methionine decreased progressively across menopausal stages (P < 0.005).
- Elevated Hcy and cysteine correlated with lower estradiol levels (r = -0.49 to -0.50, P < 0.001).
- FMD was inversely correlated with Hcy and cysteine and positively with methionine; Vitamin B12 intake correlated with FMD.
Conclusions:
- Declining estradiol during menopause may elevate Hcy and cysteine, contributing to endothelial dysfunction.
- Abnormalities in Hcy metabolism, potentially linked to B vitamin deficiencies, may exacerbate these changes.
- Cysteine may pose a greater risk to the vascular endothelium than Hcy, suggesting targeted interventions.
Abstract:
Hyperhomocysteinemia is associated with endothelial dysfunction and increased cardiovascular disease (CVD). We determined whether elevated homocysteine (Hcy) and markers of Hcy metabolism were associated with the previously reported endothelial dysfunction across stages of the menopause transition. Brachial artery flow-mediated dilation (FMD) and plasma concentrations of Hcy, cysteine, and methionine were measured in healthy women (n = 128) 22-70 yr of age categorized as premenopausal (n = 35), perimenopausal (early: n = 16; late: n = 21), and postmenopausal (early: n = 21; late: n = 35). Dietary intake of micronutrients involved in Hcy metabolism (e.g., vitamins B6, B12, folate) was assessed in a subpopulation of women. Hcy and cysteine concentrations were progressively higher, and methionine was progressively lower across menopausal stages (all P < 0.005). The higher Hcy and cysteine concentrations correlated with lower circulating estradiol levels (r = -0.49 and -0.50, respectively, both P < 0.001). FMD was inversely correlated with Hcy (r = -0.25, P = 0.004) and cysteine (r = -0.39, P < 0.001) and positively correlated with methionine concentrations (r = 0.25, P = 0.005). Dietary intake of vitamins B6 and B12 (both P < 0.05) were lower in postmenopausal women. Vitamin B12 intake correlated with FMD (r = 0.22, P = 0.006). These data suggest that declines in estradiol across stages of the menopause transition may lead to elevations in Hcy and cysteine that may contribute to endothelial dysfunction in postmenopausal women. Future studies should examine whether targeting Hcy metabolism during the perimenopausal to early postmenopausal period with interventions, including diet, attenuates or reverses the decline in endothelial function in women. NEW & NOTEWORTHY Declines in circulating estradiol across the stages of the menopausal transition may lead to elevations in Hcy and cysteine concentrations that may contribute to endothelial dysfunction. Abnormalities in the Hcy metabolic pathways, possibly related to dietary deficiencies of vitamins B12 and B6 and folate, may contribute to elevations in Hcy and cysteine concentrations. Findings also suggest that higher cysteine levels may be more damaging to the vascular endothelium than Hcy.
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