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Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress

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Abstract

Endothelial function declines progressively across stages of the menopause transition; however, the mechanisms contributing to this decline are unknown. We hypothesized that differences in endothelial function among pre-, peri, and postmenopausal women are related to differences in estradiol and oxidative stress. Brachial artery flow-mediated dilation (FMD) was measured in 87 healthy women categorized by menopause stage (24 premenopausal, 17 early and 21 late perimenopausal, and 25 postmenopausal) before and after 3 days of ovarian hormone suppression (gonadotropin releasing hormone antagonist [GnRHant]) alone, and an additional 3 days of GnRHant with concurrent transdermal estradiol or placebo add-back treatment. In 82 women, FMD during acute vitamin C (antioxidant) infusion was measured before and after GnRHant + add-back. Before GnRHant, FMD was different among groups (p < 0.005; reduced across stages of menopause). Vitamin C increased FMD in late peri- and post- (p < 0.005) but not pre- or early perimenopausal women (p > 0.54). After GnRHant alone, FMD decreased in pre- and peri- (p < 0.01), but not postmenopausal women, and was restored to premenopausal levels by estradiol add-back in the pre- and perimenopausal groups. Vitamin C improved FMD in pre-, peri-, and postmenopausal women on GnRHant + placebo. There was no effect of vitamin C on FMD in women on GnRHant + estradiol. These observations support the concept that the decline in endothelial function across the menopause transition is related to the loss of ovarian estradiol. The decline in estradiol may alter redox balance, thereby increasing oxidative stress and impairing endothelial function.

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Acknowledgments

We thank the nursing, core laboratory, bionutrition, information systems, and administrative staff of the Clinical and Translational Research Center and the Energy Balance Core of the Nutrition and Obesity Research Center for their support of the study. We also are grateful to the members of our research group who helped with the initiation of the study and carried out day-to-day activities for the project. Finally, we thank the women who volunteered to participate in the study for their time and effort.

Funding

This study was supported by the National Institutes of Health awards R01 AG027678, R56 HL114073, U54 AG062319, R01 AG049762, Colorado Clinical and Translational Sciences Institute UL1 TR001082, Colorado Nutrition and Obesity Research Center P30 DK048520, and Eastern Colorado GRECC.

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  1. Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Bldg. L15 Rm 8111, 12631 East 17th Ave., Mail Stop B179, Aurora, CO, 80045, USA

    Kerrie L. Moreau, Kerry L. Hildreth & Wendy M. Kohrt

  2. Veterans Affairs Eastern Colorado Geriatric Research, Education and Clinical Center, Denver, CO, USA

    Kerrie L. Moreau, Patrick Blatchford & Wendy M. Kohrt

  3. Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Jelena Klawitter

  4. Colorado Biostatistical Consortium, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Patrick Blatchford

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  1. Kerrie L. Moreau
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Contributions

K.L.M and W.M.K conceived and designed the research. K.L.H. provided medical oversight of the study participants, evaluated inclusion and exclusion criteria, and reviewed adverse events. J. Klawitter performed and analyzed the glutathione assays. P. Blatchford and K.L.M. performed the statistical analyses. All authors helped in the interpretation of the data, drafting of the manuscript, and approved the final version of the manuscript.

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Correspondence to Kerrie L. Moreau.

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Moreau, K.L., Hildreth, K.L., Klawitter, J. et al. Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress. GeroScience 42, 1699–1714 (2020). https://doi.org/10.1007/s11357-020-00236-7

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