Arterial Imaging Outcomes and Cardiovascular Risk Factors in Recently Menopausal Women: A Randomized Trial

Study Questions:

Is menopausal hormonal therapy associated with atherosclerosis progression and cardiovascular disease (CVD) risk factors in early menopause?


Data were from KEEPS (Kronos Early Estrogen Prevention Study), a randomized controlled trial of healthy menopausal women ages 42-58 years enrolled from nine US academic centers. Women were without clinical cardiovascular disease at baseline and were between 6 and 36 months from their final menstrual period. Women had a coronary artery calcium (CAC) score <50 Agatston units at baseline and had not received estrogen or lipid-lowering therapy for the 90 days prior to study entry. Women were randomized to oral conjugated equine estrogens (o-CEE), 0.45 mg/d, or transdermal 17β-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months. The primary endpoint was annual change in carotid artery intima–media thickness (CIMT). Secondary endpoints included changes in markers of CVD risk and change in coronary artery calcium.


Of 4,532 women contacted, 727 were randomly assigned: 230 (31.6%) to o-CEE, 222 (30.5%) to t-E2, and 275 (37.8%) to placebo. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean duration of treatment was 37.4 months for o-CEE, 34.6 months for t-E2, and 37.6 months for placebo. Participants had a mean age of 52.7 years. The majority of participants had a college degree, never smoked, and earned an annual income of $60,000 or greater. None of the baseline characteristics differed significantly among treatment groups except for the high-density lipoprotein (HDL) cholesterol level, which was lower in the placebo group. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low-density lipoprotein and HDL cholesterol levels improved and levels of C-reactive protein and sex hormone–binding globulin, but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment. Serious adverse events leading to study withdrawal included six cases of breast cancer (three in the o-CEE group, two in the t-E2 group, and one in the placebo group) among eight diagnosed cases, one transient ischemic attack in the o-CEE group, one suspected stroke (later determined not to be) in the t-E2 group, and two cases of venous thrombotic disease (one in the t-E2 group and one in the placebo group).


The investigators concluded that 4 years of early menopausal hormonal therapy did not affect progression of atherosclerosis despite improving some markers of CVD risk.


These data suggest that among women early into the postmenopausal period, menopausal hormonal therapy does not retard progression of atherosclerosis. However, as the authors note, the duration of hormonal therapy was short and the population was generally very healthy. Furthermore, data on outcomes such as stroke or myocardial infarction were not collected.

Clinical Topics: Dyslipidemia, Noninvasive Imaging, Lipid Metabolism, Nonstatins, Echocardiography/Ultrasound

Keywords: Progesterone, Follow-Up Studies, Atherosclerosis, Ischemic Attack, Transient, Estradiol, Carotid Intima-Media Thickness, Estrogens, Conjugated (USP), Interleukin-6, Breast Neoplasms, Risk Factors, Blood Pressure, Insulin Resistance, Calcium, Sex Hormone-Binding Globulin, Menopause, Cholesterol, C-Reactive Protein, Coronary Vessels

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