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Vasomotor symptoms and cardiovascular events in postmenopausal women

Szmuilowicz, Emily D. MD, MS1; Manson, JoAnn E. MD, DrPH2; Rossouw, Jacques E. MBChB, MD3; Howard, Barbara V. PhD4; Margolis, Karen L. MD, MPH5; Greep, Nancy C. MD6; Brzyski, Robert G. PhD, MD7; Stefanick, Marcia L. PhD8; O'Sullivan, Mary Jo MD9; Wu, Chunyuan MS10; Allison, Matthew MD, MPH11; Grobbee, Diederick E. MD, PhD12; Johnson, Karen C. MD, MPH13; Ockene, Judith K. PhD14; Rodriguez, Beatriz L. MD, MPH, PhD15; Sarto, Gloria E. MD, PhD16; Vitolins, Mara Z. DrPH17; Seely, Ellen W. MD18

doi: 10.1097/gme.0b013e3182014849
Original Articles

Objective: Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).

Methods: We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS).

Results: For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54).

Conclusions: Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS.

In the Women's Health Initiative Observational Study, vasomotor symptoms in perimenopausal women were associated with decreased risks of stroke, total cardiovascular disease events, and all-cause mortality. In contrast, late vasomotor symptoms were associated with increased coronary heart disease risk and all-cause mortality. The predictive value of vasomotor symptoms for clinical cardiovascular disease events may vary with the onset of vasomotor symptoms at different stages of menopause.

From the 1Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL; 2Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; 3National Heart, Lung, and Blood Institute, Bethesda, MD; 4MedStar Research Institute and Georgetown University School of Medicine, Washington, DC; 5HealthPartners Research Foundation, Minneapolis, MN; 6John Wayne Cancer Institute, Santa Monica, CA; 7Department of Obstetrics and Gynecology, University of Texas Health Sciences Center, San Antonio, TX; 8Department of Medicine, Stanford Prevention Research Center, Stanford University, Stanford, CA; 9Miller School of Medicine, University of Miami, Miami, FL; 10Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA; 11Family and Preventive Medicine, University of California, San Diego, CA; 12Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 13Department of Preventive Medicine, University of Tennessee, Health Science Center, Memphis, TN; 14Department of Medicine, University of Massachusetts Medical School, Worcester, MA; 15Departments of Geriatric Medicine, Pediatrics, and Medicine, University of Hawaii, Honolulu, HI; 16University of Wisconsin School of Medicine and Public Health, Madison, WI; 17Wake Forest University School of Medicine, Winston-Salem, NC; and 18Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Received July 24, 2010; revised and accepted September 21, 2010.

Funding/support: The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Financial disclosure/conflicts of interest: Dr. Szmuilowicz reported that she was previously a subinvestigator in a clinical trial of a diabetes treatment (glucagon-like peptide 1 agonist) sponsored by Sanofi-Aventis, and she received no financial compensation. Dr. Seely reported that she received a Bayer Health Care investigator-initiated grant. Dr. Howard reported that she is a consultant for Merck/Schering-Plough, that she received research support from the donation of drugs from Merck/Schering-Plough, and that she lectures for Merck/Schering-Plough. None of the other authors reported financial disclosures.

Address correspondence to: Emily D. Szmuilowicz, MD, MS, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, 211 E. Chicago Ave., #1050, Chicago, IL 60611. E-mail:

©2011The North American Menopause Society