title: Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol.
abstract: BACKGROUND
  Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.
  
  
  METHODS
  A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.
  
  
  RESULTS
  After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.
  
  
  CONCLUSIONS
  Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Howard N
authors.initials: HN
authors.lastname: Hodis
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Henderson
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Donna
authors.initials: D
authors.lastname: Shoupe
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Budoff
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Juliana
authors.initials: J
authors.lastname: Hwang-Levine
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Mei
authors.initials: M
authors.lastname: Feng
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Laurie
authors.initials: L
authors.lastname: Dustin
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kono
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Selzer
authors.affiliation: From the Atherosclerosis Research Unit (H.N.H., W.J.M., J.H.-L., Y.L., M.F., L.D., N.K., R.H.S., S.P.A.) and the Departments of Medicine (H.N.H.), Preventive Medicine (H.N.H., W.J.M., L.D., N.K., F.Z.S., S.P.A.), Molecular Pharmacology and Toxicology (H.N.H., J.H.-L.), and Obstetrics and Gynecology (D.S., F.Z.S.), Keck School of Medicine, University of Southern California, Los Angeles, the Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford (V.W.H.),and the Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance (M.J.B.) - all in California.
authors.forename: Stanley P
authors.initials: SP
authors.lastname: Azen
mesh_terms: D000282:Administration, Intravaginal; D000284:Administration, Oral; D050197:Atherosclerosis / Q000517:prevention & control*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D059168:Carotid Intima-Media Thickness; D003324:Coronary Artery Disease / Q000517:prevention & control*; D018450:Disease Progression; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects*; D011374:Progesterone / Q000008:administration & dosage
chemical_list: D011374:Progesterone; D004958:Estradiol