Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women's health initiative trials of hormone therapy
Open accessAbstract
BACKGROUND: Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit. METHODS: This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus. RESULTS: In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events. CONCLUSIONS: Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.
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Long-term and recent hormone use can affect biomarker profiles.
“In addition, long-term and recent hormone use can affect biomarker profiles (41–43)”
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Cites
Writing Group for the Women's Health Initiative Investigators (2002) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.288.3.321 · Cited by 15,889 · see citing works
Hulley, S. (1998) · JAMA · doi:10.1001/jama.280.7.605 · Cited by 6,216 · see citing works
Estrogen plus Progestin and the Risk of Coronary Heart Disease
Manson, J. E., Hsia, J., Johnson, K. C., Rossouw, J. E., Assaf, A. R., Lasser, N. L., Trevisan, M., Black, H. R., Heckbert, S. R., Detrano, R., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030808 · Cited by 2,065 · see citing works
Self-citationPostmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause
Rossouw, J. E., Prentice, R. L., Manson, J. E., Wu, L., Barad, D., Barnabei, V. M., Ko, M., LaCroix, A. Z., Margolis, K. L., & Stefanick, M. L. (2007) · JAMA · doi:10.1001/jama.297.13.1465 · Cited by 1,741 · see citing works
Self-citationMolecular and Cellular Basis of Cardiovascular Gender Differences
Mendelsohn, M. E., & Karas, R. H. (2005) · Science · doi:10.1126/science.1112062 · Cited by 1,101 · see citing works
Tracy, R. P., Lemaitre, R. N., Psaty, B. M., Ives, D. G., Evans, R. W., Cushman, M., Meilahn, E. N., & Kuller, L. H. (1997) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.17.6.1121 · Cited by 836 · see citing works
Self-citationWeiss, E. J., Bray, P. F., Tayback, M., Schulman, S. P., Kickler, T. S., Becker, L. C., Weiss, J. L., Gerstenblith, G., & Goldschmidt‐Clermont, P. J. (1996) · New England Journal of Medicine · doi:10.1056/nejm199604253341703 · Cited by 688 · see citing works
Self-citationConjugated Equine Estrogens and Coronary Heart Disease
Hsia, J. A. (2006) · Archives of Internal Medicine · doi:10.1001/archinte.166.3.357 · Cited by 604 · see citing works
Self-citation27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen
Umetani, M., Domoto, H., Gormley, A. K., Yuhanna, I. S., Cummins, C. L., Javitt, N. B., Korach, K. S., Shaul, P. W., & Mangelsdorf, D. J. (2007) · Nature Medicine · doi:10.1038/nm1641 · Cited by 397 · see citing works
Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women
Mosca, L. J., Appel, L. J., Benjamin, E. J., Berra, K. A., Chandra‐Strobos, N., Fabunmi, R. P., Grady, D. G., Haan, C. K., Hayes, S. N., Judelson, D. R., et al. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000114834.85476.81 · Cited by 342 · see citing works
Fibrinolytic Activation Markers Predict Myocardial Infarction in the Elderly
Cushman, M., Lemaître, R. N., Kuller, L. H., Psaty, B. M., Macy, E. M., Sharrett, A. R., & Tracy, R. P. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.3.493 · Cited by 250 · see citing works
Self-citationTracy, R. P., Arnold, A. M., Ettinger, W. H., Fried, L. P., Meilahn, E. N., & Savage, P. J. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.7.1776 · Cited by 198 · see citing works
Rautaharju, P. M., Park, L. P., CHAITMAN, B. R., Rautaharju, F., & Zhang, Z. (1998) · Journal of Electrocardiology · doi:10.1016/s0022-0736(98)90132-7 · Cited by 143 · see citing works
Yano, K., Grove, J. S., Chen, R., Rodriguez, B. L., Curb, J. D., & Tracy, R. P. (2001) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.21.6.1065 · Cited by 76 · see citing works
Hsia, J. A., Otvos, J. D., Rossouw, J. E., Wu, L., Wassertheil-Smoller, S. W., Hendrix, S. L., Robinson, J. G., Lund, B., & Kuller, L. H. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.170431 · Cited by 55 · see citing works
Self-citationCan Biomarkers Identify Women at Increased Stroke Risk? The Women's Health Initiative Hormone Trials
Kooperberg, C. L., Cushman, M., Hsia, J. A., Robinson, J. G., Aragaki, A. K., Lynch, J. K., Baird, A. E., Johnson, K., Kuller, L. H., Beresford, S. A. A., et al. (2007) · PLoS Clinical Trials · doi:10.1371/journal.pctr.0020028 · Cited by 36 · see citing works
Self-citationEstrogen plus progestin and risk of coronary heart disease
Manson, J. E. (2004) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2004.03.003 · Cited by 20 · see citing works
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Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline
Stuenkel, C. A., Davis, S. R., Gompel, A., Lumsden, M. A., Murad, M. H., Pinkerton, J. V., & Santen, R. J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2236 · Cited by 884 · see citing works
Juster, R.-P., Bizik, G., Picard, M., Arsenault-Lapierre, G., Sindi, S., Trepanier, L., Marin, M.-F., Wan, N., Sekerovic, Z., Lord, C., et al. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000289 · Cited by 268 · see citing works
Vitonis, A. F., Vincent, K., Rahmioglu, N., Fassbender, A., Buck Louis, G. M., Hummelshoj, L., Giudice, L. C., Stratton, P., Adamson, G. D., Becker, C. M., et al. (2014) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.07.1244 · Cited by 236 · see citing works
- Authors
- Rossouw, J. E., Cushman, M., Greenland, P., Lloyd-Jones, D. M., Bray, P., Kooperberg, C., Pettinger, M., Robinson, J., Hendrix, S., & Hsia, J.
- Affiliations
- National Heart, Lung, and Blood Institute (US)
- University of Vermont (US)
- Northwestern University (US)
- Thomas Jefferson University (US)
- Fred Hutch Cancer Center (US)
- University of Iowa (US)
- Wayne State University (US)
- AstraZeneca (United Kingdom) (GB)
- ORCID
- Venue
- Archives of Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2008-11-10
- Volume
- 168
- Issue
- 20
- Pages
- 2245
- ISSN
- 0003-9926 (ISSN-L)
- PMC
- PMC2726792
- OpenAlex
- W2110389637
- Cited by
- 85
- References
- 18
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 12 · 2012: 7
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01wh22110-38-0-0, N01 WH022110)
- U.S. Public Health Service (44221, 32122, 24152, 42107-26, 42129-32, 32118-32119, 32100-2, 32105-6, 32108-9, 32111-13, 32115)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- coronary artery disease, hormone replacement therapy, inflammatory markers, lipid biomarkers, thrombotic biomarkers, genetic polymorphism, LDL cholesterol, conjugated equine estrogens, interleukin-6, MMP-9, D-dimer, von Willebrand factor, homocysteine, insulin, Women's Health Initiative
- MeSH terms
- Aged, Cholesterol, Coronary Disease, Estrogens, Conjugated (USP), Factor VIII, Female, Fibrin Fibrinogen Degradation Products, Homocysteine, Humans, Hysterectomy, Inflammation, Insulin, Leukocyte Count, Cholesterol, HDL, Cholesterol, LDL, Medroxyprogesterone, Middle Aged, Polymorphism, Genetic, Thrombosis, Triglycerides, von Willebrand Factor, Biomarkers, Interleukin-6, Estrogen Replacement Therapy, Case-Control Studies, Matrix Metalloproteinase 9, Integrin beta3
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