title: Dose-dependent toxic effects of high-dose estrogen on renal and cardiac injury in surgically postmenopausal mice.
abstract: OBJECTIVE
  We previously found that in mice with experimental myocardial infarction (MI), 17β-estradiol (E2) increased mortality and worsened cardiac remodeling and these deleterious effects were associated with renal enlargement and hydronephrosis in a dose-dependent manner. In the present study we questioned whether E2-induced renal damage predisposes to rather than results from its adverse effects on the heart.
  
  
  METHODS
  Ovariectomized (ovx) mice received either placebo (P) or E2 at 0.02 (E2-L, low dose), 0.42 (E2-M, moderate dose) or 4.2 μg/d (E2-H, high dose) for 8 weeks.
  
  
  RESULTS
  E2-L partially restored uterine weight and plasma estrogen levels without affecting heart, lung and liver weight, hemodynamic parameters, or heart and kidney morphology and function. E2-M restored normal uterine weight, but this was accompanied by a significant increase in kidney weight, albuminuria, glomerular matrix formation and markers for oxidative stress. E2-H increased uterine weight 4.5-fold and resulted in higher plasma creatinine levels, severe albuminuria, renal tubular dilatation, tubulointerstitial injury, hydronephrosis, glomerulosclerosis and oxidative stress. E2-H also caused ascites, hepatomegaly and fluid retention in the uterine horns but had no significant effect on blood pressure or heart function.
  
  
  CONCLUSIONS
  Our data demonstrated that an excessive dose of E2 that raises uterine weight beyond physiological levels adversely affects the kidney even before it damages the heart. We believe estrogen dosage should be taken into account when considering hormonal replacement therapy, since inappropriate doses of E2 may damage not only the heart but also the kidney.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Meng
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Dai
authors.forename: Tang-Dong
authors.initials: TD
authors.lastname: Liao
authors.forename: Martin
authors.initials: M
authors.lastname: D'Ambrosio
authors.forename: Fangfei
authors.initials: F
authors.lastname: Wang
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
mesh_terms: D000419:Albuminuria / Q000139:chemically induced; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000633:toxicity*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000097:blood; D005260:Female; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D017698:Postmenopause / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D004967:Estrogens; D004958:Estradiol; D003404:Creatinine