• Hormone Replacement Therapy (HRT): Does It Reduce Heart Disease Risk in Postmenopausal Women?

    pill bottle Not long ago, the medical community promoted HRT as something that could help postmenopausal women reduce their risk of heart disease. Now research suggests that HRT might not help reduce the risk of heart disease in postmenopausal women and might even increase it. How do you make sense of it all?
    Cardiovascular disease, primarily coronary artery disease , is the leading cause of death among women in the US. After menopause , the incidence of cardiovascular disease increases sharply among women—something that medical scientists have speculated relates to the large drop in hormone levels. Over the past few decades, many observational studies (clinical studies in which the treatment observed is not compared to other treatments or placebos) have suggested that HRT helps protect postmenopausal women from cardiovascular disease. However, newer and more scientifically rigorous studies have been providing evidence to the contrary.

    Uses of HRT

    HRT generally consists of a combination of the hormone estrogen (estrogen replacement therapy or ERT) and progesterone, especially in women who still have a uterus. Women without a uterus may receive estrogen alone. HRT is often used on a short-term basis for the relief of unpleasant menopausal symptoms such as hot flashes, vaginal dryness, and irritability. HRT has been used by postmenopausal women on a long-term basis, with the assumption that it would reduce their risk of osteoporosis and heart disease.

    The Latest Evidence

    Despite medical scientists’ previous beliefs about the cardiovascular benefits of HRT, newer and better-designed studies have been showing evidence to the contrary. Three studies have shown no cardiovascular benefit among women randomly assigned to HRT, while some even show increased rates of cardiovascular disease in the group taking HRT. These studies include the following:

    The Heart and Estrogen/Progestin Replacement Study (HERS)

    The Heart and Estrogen/Progestin Replacement Study (HERS-I), reported in the Journal of the American Medical Association (JAMA), looked at 2,763 postmenopausal women with pre-existing coronary artery disease who were randomly assigned to take either estrogen/progestin HRT or a placebo (secondary prevention trial).
    Researchers found that the women receiving HRT actually had a higher risk of heart attacks and cardiac events during the first year of the study, compared to women taking the placebo. During the next 4-5 years of the study, however, the risk for women in the HRT group diminished. At the end of 4.1 years, researchers found no overall reduction in the rate of coronary heart disease events among the women receiving HRT compared to those receiving the placebo, despite that fact that HRT reduced LDL (“bad”) cholesterol while increasing levels of HDL (“good”) cholesterol.
    In 2002, a follow-up study was published in JAMA. The Heart and Estrogen/Progestin Replacement Study (HERS-II) examined an additional 2.7 years. In contrast to the first findings, the researchers discovered that the HRT group failed to reduce the risk of cardiovascular events as compared to the placebo group. Therefore, HRT should not be prescribed in postmenopausal women to reduce cardiovascular risk.

    The Estrogen Replacement and Atherosclerosis (ERA) Trial

    The Estrogen Replacement and Atherosclerosis (ERA) Trial was another randomized trial comparing HRT to a placebo (secondary prevention trial). Among the 309 postmenopausal women with pre-existing coronary artery disease, the study failed to show any cardiac benefit with HRT, in spite of the fact that the women receiving HRT in the study had a significant increase in HDL cholesterol and a decrease in LDL cholesterol—two markers that usually indicate a lower risk of coronary artery disease.

    Women’s Health Initiative Study (WHI)

    The July 2002 issue of the Journal of the American Medical Association (JAMA) reported results from the Women’s Health Initiative Study. This randomized trial compared HRT to a placebo in 16,608 postmenopausal women with no pre-existing coronary artery disease (primary prevention trial). After an average follow-up of 5.2 years, researchers found that the HRT group had 29% more heart attacks, 41% more strokes , and double the number of blood clots than did the placebo group. Although the actual cardiovascular risk associated with HRT for each individual appears to be low, small risks over time, when applied to a large group of people, could add up to a significant number of serious cardiovascular events.
    A 2004 follow-up study, WHI-CEE, consisted of 10,739 postmenopausal women, aged 50-79 years. These women, who had a prior hysterectomy, were given 0.625 mg/day of conjugated equine estrogen (CEE) or placebo. The key findings include:
    • CEE increased the risk of stroke
    • CEE reduced the risk of hip fracture
    • CEE did not reduce the risk of coronary heart disease
    The overall conclusion is that CEE should not be given to postmenopausal women to prevent heart disease.

    What Does This Mean for Women and Their Doctors?

    Where does the latest evidence leave postmenopausal women and their doctors? The American Heart Association offers the following recommendations for postmenopausal hormone therapy:
    • HRT should not be used to prevent cardiovascular disease in women who have no signs of heart disease.
    • HRT should not be used to try to prevent a second heart attack or death among women with established heart disease.
    • HRT should not be used in women who have had an ischemic stroke or transient ischemic attack.
    • The benefits of long-term HRT for preventing osteoporosis and broken bones must be weighed against the risks of cardiovascular disease and breast cancer. Therefore, other options for bone health should be considered.
    • Short-term use of HRT for relief of menopausal symptoms may be worth a small increase in risk for heart disease and breast cancer; however, it should be used for the shortest time necessary at the lowest effective dosage.
    • Women should consult their doctors before making any decisions about HRT.

    How Can You Reduce the Risk of Cardiovascular Disease?

    In place of HRT, the American Heart Association and the National Heart, Lung, and Blood Institute recommend established methods for lowering heart disease risk in women:
      Lifestyle behaviors, such as:
      • Following a healthy diet (including omega-3 fats, soy, fiber, oats, walnuts, cholesterol-lowering margarines, and other beneficial dietary components)
      • Limiting consumption of alcoholic beverages (although 6-12 ounces of red wine a day has heart health benefits)
      • Not smoking
      • Maintaining a healthy weight
      • Being physically active
    • Preventing and controlling high blood pressure
    • Preventing and controlling high cholesterol
    • Managing diabetes
    • Taking prescribed medications, such as aspirin, statins, beta-blockers, and ACE inhibitors to prevent or control heart disease
    The long-term cardiac effects of HRT are still unknown, especially for women with no pre-existing coronary artery disease. It’s possible that the HDL cholesterol-increasing and LDL cholesterol-lowering effects of HRT may prove to be beneficial in the long-term. In the meantime, decision-making must be made on the current best evidence— large, well designed, randomized placebo controlled trials—rather than observational studies.


    American Heart Association http://www.americanheart.org/

    National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/


    Heart and Stroke Foundation of Canada http://www.heartandstroke.com/

    Women's Health Matters http://www.womenshealthmatters.ca/


    Estrogen replacement and atherosclerosis trial (ERA). American College of Cardiology Website. Available at: http://www.acc.org/education/online/trials/acc2000/ERA.htm . Accessed January 30, 2003.

    Facts about postmenopausal hormone therapy. National Heart, Lung, and Blood Institute website. Available at: http://www.nhlbi.nih.gov/health/women/pht%5Ffacts.htm . Accessed January 30, 2003.

    Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2010 October 21. Available at: http://stroke.ahajournals.org/cgi/reprint/STR.0b013e3181f7d043v1. Updated October 21, 2010. Accessed November 2, 2010.

    Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy (HERS-II). JAMA. 2002;288:49-57.

    Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613.

    Questions and answers about postmenopausal hormone therapy. American Heart Association website. Available at: http://www.americanheart.org/ . Accessed January 30, 2003.

    The Women’s Health Initiative Sterring Committee: Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy (WHI-CEE Trial). JAMA. 2004;291:1701-1712.

    Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002;288:321-333.

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