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One of the main arguments against extrapolation of the Women’s Health Initiative (WHI) study data to the whole postmenopausal population was that it actually focused on the 60+ year-old women who were treatment-naïve until then [1], whereas in real life most hormone users are 45–55 years old at initiation of therapy. The Kronos Early Estrogen Prevention Study (KEEPS) was designed to provide information on the effects of hormone therapy (HT) in recently menopausal women. Results from KEEPS are now published in the literature [2]. The main aim of KEEPS was to assess atherosclerosis progression and cardiovascular risk factors after HT initiation. The study enrolled 727 healthy menopausal women aged 42–58 years (mean 52.7 years), between 6 and 36 months from last menses, without prior cardiovascular disease events, who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days. Study medications included oral conjugated equine estrogens (o-CEE), 0.45 mg/day, or transdermal 17β-estradiol (t-E2), 50 μg/day, 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 cardiovascular disease risk. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom the 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 (LDL) and high density lipoprotein (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. Power to compare clinical events was insufficient. Thus 4 years of early HT did not affect progression of atherosclerosis despite improving some markers of cardiovascular disease risk.


  • Amos Pines
    Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  • Fred Naftolin
    Professor of Obstetrics and Gynecology, and Environmental Medicine, Director, Reproductive Biology Research, Co-Director, NYU Interdisciplinary Program in Menopause Medicine, New York University, New York, USA
  • JoAnn E. Manson
    Professor of Obstetrics and Gynecology, and Environmental Medicine, Director, Reproductive Biology Research, Co-Director, NYU Interdisciplinary Program in Menopause Medicine, New York University, New York, USA
  • Roger Lobo
    Department of Obstetrics & Gynecology, Columbia University, New York, New York, USA


  1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
  2. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014 Jul 29. Epub ahead of print.
  3. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008;168:1333-9.
  4. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-53.
  5. Espeland MA, Applegate W, Furberg CD, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study. Am J Epidemiol 1995;142:1011-19.
  6. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-602.
  7. Ge Q, Tian Q, Tseng H, Naftolin F. Development of low-dose reproductive hormone therapies in China. Gynecol Endocrinol 2006;22:636-45
  8. Tan O, Harman SM, Naftolin F. What can we learn from design faults in the Womens Health Initiative randomized clinical trial? Bull NYU Hosp Jt Dis 2009;67:226-9
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