Symposium
Hormone Replacement Therapy and Coronary Heart Disease in Women: A Review of the Evidence

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It is well documented that coronary heart disease (CHD) is the leading cause of death in women—especially postmenopausal women. The role of hormone replacement therapy (HRT) in prevention of CHD has been considered for many years. Early epidemiological studies suggested estrogen to have a potential cardioprotective role, noting that premenopausal women have a decreased risk of developing CHD compared with men. Later observational studies showed decrease of CHD risk in postmenopausal women on HRT. By 1996, estrogen (specifically Premarin) was one of the most dispensed medications in the United States. Major medical organizations such as the American College of Physicians and American College of Obstetricians and Gynecologists widely endorsed and encouraged HRT for CHD risk reduction, along with using HRT for other potential benefits (such as osteoporosis prevention). Unfortunately, recent clinical trials seem to raise more questions than provide definitive proof in the protective role of estrogen in CHD. A review of recent and ongoing observational studies and clinical trials may help guide physicians in their recommendation and discussion of the role of HRT in postmenopausal women. As this article was being prepared for publication, reports from both the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) and the Women’s Health Initiative (WHI) were published. Both studies concluded that HRT has no role in primary or secondary prevention of CHD in women.

Section snippets

Early Studies/Observational Studies

The role of hormone replacement therapy (HRT) in prevention of CHD was first considered when early epidemiological studies indicated a possible protective role of estrogen. Premenopausal women with intact ovaries presented with CHD 10 years later than men of the same age, 6 whereas women who underwent bilateral oophorectomy had CHD rates comparable with those of men of the same age. 7 Another study showed a 2% decrease in cardiovascular mortality rate for every year’s delay in development of

Clinical Trials

The first randomized trial to assess the role of HRT on secondary prevention of CHD was actually conducted in men with prior history of Q-wave MI, who were randomized to receive estrogen or placebo. 19 The study was prematurely discontinued because of a significant increase in MI as well as increase in thromboembolic disease in the group receiving estrogen.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial was the first large randomized trial in women to look at the effect of HRT

Other Hormones and CHD

There has been increasing interest in selective estrogen receptor modulators (SERMs) as a substitute for estrogen. The SERMs role in CHD is not yet well defined. Several ongoing trials are examining the potential relationship between SERM and CHD.

In the Breast Cancer Prevention Trial (BCPT), 13,388 women >60 years old with high risk for breast cancer were randomized to tamoxifen or placebo. 25 The primary outcome of the study was breast cancer prevention; CHD events were secondary outcomes of

Discussion

The beneficial role of estrogen in CHD has been considered for many years, but recent studies bring forth many unanswered questions. Based on early epidemiological studies, it seemed logical to conclude that HRT has a protective role for women against CHD. Subsequent observational studies have supported this hypothesis. However, limitations and flaws intrinsic to observational studies may have caused significant bias and thus affected interpretation of the data. In observational studies, such

Update

As this article was being prepared for publication, reports from both Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) 29 and Women’s Health Initiative (WHI) 30 were published. Both studies concluded that HRT has no role in primary or secondary prevention of CHD in women.

HERS II was designed to determine whether the CHD risk reduction observed in the later years of HERS will persist over long-term use of HRT. The study followed HERS women who continued on HRT for an additional

References (30)

  • KannelW.B.

    Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study

    Am Heart J

    (1987)
  • van der SchouwY.T. et al.

    Age at menopause as a risk factor for cardiovascular mortality

    Lancet

    (1996)
  • MoscaL. et al.

    Design methods of the Raloxifene Use for The Heart (RUTH) study

    Am J Cardiol

    (2001)
  • HoyertD.L. et al.

    Deaths: final data for 1997

    Natl Vital Stat Rep

    (1999)
  • Gallop Survey conducted for the American Women’s Medical Association

    (1995)
  • GradyD. et al.

    Hormone therapy to prevent disease prolong life in postmenopausal women

    Ann Intern Med

    (1992)
  • ChandraN.C. et al.

    Observations of the treatment of women in the United States with myocardial infarction.A report from the National Registry of Myocardial Infarction-I

    Arch Intern Med

    (1998)
  • MarrugatJ. et al.

    Mortality differences between men women following first myocardial infarction

    JAMA

    (1998)
  • WuerstJ.H. et al.

    The degree of coronary atherosclerosis in bilaterally oophorectomized women

    Circulation

    (1953)
  • GenantH. et al.

    Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentration, endometrium, lipid levels.Estratab/Osteoporosis Study Group

    Arch Intern Med

    (1997)
  • ChaeC.U. et al.

    Postmenopausal hormone replacement therapy cardiovascular disease

    Thromb Haemost

    (1997)
  • ShlipakM.G. et al.

    Estrogen progestin, lipoprotein(a), the risk of recurrent coronary heart disease events after menopause

    JAMA

    (2000)
  • MendelsohnM.E. et al.

    The protective effects of estrogen on the cardiovascular system

    N Engl J Med

    (1999)
  • Barrett-ConnorE. et al.

    Hormone replacement therapy, heart disease, other considerations

    Annu Rev Public Health

    (1998)
  • StampferM.J. et al.

    A prospective study of postmenopausal estrogen therapy coronary heart disease

    N Engl J Med

    (1985)
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