title: Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis.
abstract: OBJECTIVE
  To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause.
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17β-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition.
  
  
  RESULTS
  A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (-0.06, 95% confidence interval -0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late postmenopause groups (2-tailed interaction p = 0.88). Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition.
  
  
  CONCLUSIONS
  Estradiol initiated within 6 years of menopause does not affect verbal memory, executive functions, or global cognition differently than therapy begun 10+ years after menopause. Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause.
  
  
  METHODS
  This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10+ years after menopause.
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles. vhenderson@stanford.edu.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Henderson
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Jan A
authors.initials: JA
authors.lastname: St John
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Howard N
authors.initials: HN
authors.lastname: Hodis
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Carol A
authors.initials: CA
authors.lastname: McCleary
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Donna
authors.initials: D
authors.lastname: Shoupe
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kono
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Laurie
authors.initials: L
authors.lastname: Dustin
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.affiliation: From the Departments of Health Research & Policy (Epidemiology) and Neurology & Neurological Sciences (V.W.H.), Stanford University; Atherosclerosis Research Unit (J.A.S., H.N.H., N.K., L.D., H.A., W.J.M.) and Departments of Preventive Medicine (J.A.S., H.N.H., F.Z.S., N.K., L.D., H.A., W.J.M.), Medicine (H.N.H.), Neurology (C.A.M.), and Obstetrics and Gynecology (F.Z.S., D.S.), Keck School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (H.N.H.), University of Southern California, Los Angeles.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
mesh_terms: D000368:Aged; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000379:methods*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D056344:Executive Function / Q000187:drug effects*; D005500:Follow-Up Studies; D006801:Humans; D061212:Memory, Episodic; D008593:Menopause; D008875:Middle Aged; D017698:Postmenopause; D011374:Progesterone / Q000008:administration & dosage; D011372:Progestins / Q000008:administration & dosage; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D004967:Estrogens; D011372:Progestins; D014622:Vaginal Creams, Foams, and Jellies; D011374:Progesterone; D004958:Estradiol