title: Early, but not late onset estrogen replacement therapy prevents oxidative stress and metabolic alterations caused by ovariectomy.
abstract: OBJECTIVE
  The usefulness of estrogen replacement therapy (ERT) in preventing oxidative stress associated with menopause is controversial. We aimed to study if there is a critical time window for effective treatment of the effects of ovariectomy with estrogens at the molecular, metabolic, and cellular level.
  
  
  RESULTS
  Our main finding is that early, but not late onset of ERT prevents an ovariectomy-associated increase in mitochondrial hydrogen peroxide levels, oxidative damage to lipids and proteins, and a decrease in glutathione peroxidase and catalase activity in rats. This may be due to a change in the estrogen receptor (ER) expression profile: ovariectomy increases the ER α/β ratio and immediate estrogen replacement prevents it. Positron emission tomography analysis shows that ovariectomy decreases the brain glucose uptake in vivo and that estrogen administration is beneficial, but only if administered immediately after deprivation. Ovariectomy decreases GLUT-1 and 3 glucose transporters in the brain, and only early onset estrogen administration prevents it. Plasma from rats treated with estrogens immediately after ovariectomy show similar metabolomics profiles as controls.
  
  
  METHODS
  We provide molecular basis for the recommendation of early onset ERT and explain its lack of effectiveness if a significant time period elapses after ovariectomy and probably after the onset of menopause.
  
  
  CONCLUSIONS
  Only early, but not late onset administration of estrogens after ovariectomy has beneficial effects at molecular levels on oxidative stress, brain glucose uptake, and metabolomic profiles.
authors.affiliation: 1 Department of Physiology, School of Medicine, University of Valencia/INCLIVA , Valencia, Spain .
authors.forename: Raúl
authors.initials: R
authors.lastname: López-Grueso
authors.forename: Juan
authors.initials: J
authors.lastname: Gambini
authors.forename: Kheira M
authors.initials: KM
authors.lastname: Abdelaziz
authors.forename: Daniel
authors.initials: D
authors.lastname: Monleón
authors.forename: Ana
authors.initials: A
authors.lastname: Díaz
authors.forename: Marya
authors.initials: M
authors.lastname: El Alami
authors.forename: Vicent
authors.initials: V
authors.lastname: Bonet-Costa
authors.forename: Consuelo
authors.initials: C
authors.lastname: Borrás
authors.forename: José
authors.initials: J
authors.lastname: Viña
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage*; D015914:Estrogen Replacement Therapy; D005260:Female; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D055432:Metabolomics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats
chemical_list: D000975:Antioxidants; D051246:Glucose Transport Proteins, Facilitative; D004958:Estradiol; D006861:Hydrogen Peroxide; D005947:Glucose