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Cited by 134Menopause: Health Impacts and TreatmentsDiabetes, Cardiovascular Risks, and LipoproteinsHormonal and reproductive studies

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Metabolic characterization of menopause: cross-sectional and longitudinal evidence

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Wang, Qin, Ferreira, Diana L. Santos, Nelson, Scott M., Sattar, Naveed, Ala-Korpela, Mika, Lawlor, Debbie A.·2018·BMC Medicine
DOI 10.1186/s12916-018-1008-8PMC PMC5800033

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Abstract

BACKGROUND: Women who experience menopause are at higher cardiometabolic risk and often display adverse changes in metabolic biomarkers compared with pre-menopausal women. It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging. Well-conducted longitudinal studies are required to determine this. The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status, defined according to the 2012 Stages of Reproductive Aging Workshop criteria, with 74 metabolic biomarkers, and establish whether any associations are independent of age-related changes. METHODS: We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women. In a subgroup of 1,492 women who had repeat assessments after 2.5 years, we assessed how the change in reproductive status was associated with the changes in metabolic biomarkers. Metabolic profiles were measured by high-throughput quantitative nuclear magnetic resonance metabolomics. In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive-status category change to that of the reference of being pre-menopausal at both time points. As all women aged by a similar amount during follow-up, these analyses contribute to distinguishing age-related changes from those related to change in reproductive status. RESULTS: Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting the transition to menopause induces multiple metabolic changes independent of chronological aging. The metabolic changes included increased concentrations of very small very low-density lipoproteins, intermediate-density lipoproteins, low-density lipoproteins (LDLs), remnant, and LDL cholesterol, and reduced LDL particle size, all toward an atherogenic lipoprotein profile. Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein. Also, levels of glutamine and albumin increased during the transition. Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years. CONCLUSIONS: The transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory. The adverse changes in multiple apolipoprotein-B-containing lipoprotein subclasses and increased inflammation may underlie women's increased cardiometabolic risk in their post-menopausal years.

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Figures

Fig. 1 Participant flow and study design. a Participant flow into eligible and analysis groups. b Study design and reproductive status defined by STRAW criteria. HRT hormone replacement therapy, MT menopausal transition, PostM post-menopausal, PreM pre-menopausal
Fig. 1 Participant flow and study design. a Participant flow into eligible and analysis groups. b Study design and reproductive status defined by STRAW criteria. HRT hormone replacement therapy, MT menopausal transition, PostM post-menopausal, PreM pre-menopausalCC BY · PubMed Central
Fig. 2 Heat map of metabolic concentrations across age groups (top panel) and across reproductive categories (bottom panel). Top panel: age groups are largely in 1-year age categories (at the extremes of age range, groups were collapsed because of small numbers: 34 to 38 years and 59 to 63 years). For each metabolic measure, mean metabolite concentrations across each age group are displayed in colors. The horizontal black line marks the typical age of natural menopause in Europe. Bottom panel: reproductive categories are defined according to the STRAW criteria. For each metabolic measure, mean metabolite concentrations across each menopausal category are displayed in colors. The age range of each reproductive category is shown on the y-axis. As the metabolic measures were scaled to SD units, both analyses (aging and menopause) thus used the population mean of all women at baseline as the reference value, marked as white boxes in the plots. The metabolic measures in both panels are plotted in the same order. C cholesterol, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, TG triglycerides, VLDL very low-density lipoprotein
Fig. 2 Heat map of metabolic concentrations across age groups (top panel) and across reproductive categories (bottom panel). Top panel: age groups are largely in 1-year age categories (at the extremes of age range, groups were collapsed because of small numbers: 34 to 38 years and 59 to 63 years). For each metabolic measure, mean metabolite concentrations across each age group are displayed in colors. The horizontal black line marks the typical age of natural menopause in Europe. Bottom panel: reproductive categories are defined according to the STRAW criteria. For each metabolic measure, mean metabolite concentrations across each menopausal category are displayed in colors. The age range of each reproductive category is shown on the y-axis. As the metabolic measures were scaled to SD units, both analyses (aging and menopause) thus used the population mean of all women at baseline as the reference value, marked as white boxes in the plots. The metabolic measures in both panels are plotted in the same order. C cholesterol, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, TG triglycerides, VLDL very low-density lipoproteinCC BY · PubMed Central
Fig. 3 Cross-sectional (top panel) and longitudinal (bottom panel) associations of reproductive categories with 74 metabolic measures. Top panel: In the cross-sectional analysis, women were categorized into pre-menopausal, menopausal transition, and post-menopausal groups. Using pre-menopausal women as the reference group, the colors define the SD differences in each metabolite concentration between the other two groups and the reference group (Fig. 1b). Bottom panel: In the longitudinal analysis, women were categorized into six groups based on their baseline and follow-up reproductive status. Using those women who were pre-menopausal at both time points as the reference group, the colors illustrate the SD differences in the concentration change during the follow-up between the other five groups and the reference group (Fig. 1b). Cross-sectional and longitudinal associations were adjusted for baseline age. The metabolites are plotted in the same order as in Fig. 2. C cholesterol, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, SD standard deviation, TG triglycerides, VLDL very low-density lipoprotein
Fig. 3 Cross-sectional (top panel) and longitudinal (bottom panel) associations of reproductive categories with 74 metabolic measures. Top panel: In the cross-sectional analysis, women were categorized into pre-menopausal, menopausal transition, and post-menopausal groups. Using pre-menopausal women as the reference group, the colors define the SD differences in each metabolite concentration between the other two groups and the reference group (Fig. 1b). Bottom panel: In the longitudinal analysis, women were categorized into six groups based on their baseline and follow-up reproductive status. Using those women who were pre-menopausal at both time points as the reference group, the colors illustrate the SD differences in the concentration change during the follow-up between the other five groups and the reference group (Fig. 1b). Cross-sectional and longitudinal associations were adjusted for baseline age. The metabolites are plotted in the same order as in Fig. 2. C cholesterol, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, SD standard deviation, TG triglycerides, VLDL very low-density lipoproteinCC BY · PubMed Central
Fig. 4 Cross-sectional (blue) and longitudinal (red) associations of natural menopause with 74 metabolic measures. The cross-sectional associations are differences in mean metabolites comparing post-menopausal to pre-menopausal women. The longitudinal associations are the differences in mean differences over time comparing four groups meta-analyzed together (pre-menopause to menopause transition, menopause transition at both times, menopause transition to post-menopause, and pre-menopause to post-menopause) to pre-menopause at both times (the reference group). The meta-analysis of the four groups, each of which at least partly represent the transition process from pre-menopausal to post-menopausal, was used to increase statistical power. Cross-sectional and longitudinal associations were adjusted for baseline age. C cholesterol, CI confidence interval, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, SD standard deviation, TG triglycerides, VLDL very low-density lipoprotein
Fig. 4 Cross-sectional (blue) and longitudinal (red) associations of natural menopause with 74 metabolic measures. The cross-sectional associations are differences in mean metabolites comparing post-menopausal to pre-menopausal women. The longitudinal associations are the differences in mean differences over time comparing four groups meta-analyzed together (pre-menopause to menopause transition, menopause transition at both times, menopause transition to post-menopause, and pre-menopause to post-menopause) to pre-menopause at both times (the reference group). The meta-analysis of the four groups, each of which at least partly represent the transition process from pre-menopausal to post-menopausal, was used to increase statistical power. Cross-sectional and longitudinal associations were adjusted for baseline age. C cholesterol, CI confidence interval, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, MUFA monounsaturated fatty acids, PL phospholipids, PUFA polyunsaturated fatty acids, SD standard deviation, TG triglycerides, VLDL very low-density lipoproteinCC BY · PubMed Central

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Metadata

Authors
Wang, Q., Ferreira, D. L. S., Nelson, S. M., Sattar, N., Ala-Korpela, M., & Lawlor, D. A.
Affiliations
  • University of Oulu (FI)
  • University of Bristol (GB)
  • University of Glasgow (GB)
Corresponding author
Lawlor, Debbie A.
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-02-06
Volume
16
Issue
1
Pages
17-17
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-018-1008-8
PMC
PMC5800033
OpenAlex
W2757552189
Cited by
134
References
48
Citations by year
2026: 10 · 2025: 15 · 2024: 14 · 2023: 18 · 2022: 23 · 2021: 20 · 2020: 18 · 2019: 12 · 2018: 4
FWCI
10.75
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Explore Bristol Research (submittedVersion, cc-by)
Funders
  • British Heart Foundation (SP/07/008/24066)
  • Wellcome (WT092830M)
  • UK Medical Research Council (G1001357)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
menopause, perimenopause, metabolic biomarkers, cardiometabolic risk, ovarian aging, chronological aging, lipoprotein profile, atherogenic lipoproteins, LDL particle size, remnant cholesterol, inflammation, glycoprotein acetyls, glutamine, albumin, postmenopausal women
MeSH terms
Adult, Aged, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Menopause, Middle Aged

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