title: Can biomarkers identify women at increased stroke risk? The Women's Health Initiative Hormone Trials.
abstract: OBJECTIVE
  The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT).
  
  
  METHODS
  The hormone trials were randomized, double-blind, and placebo controlled.
  
  
  METHODS
  The Women's Health Initiative trials were conducted at 40 clinical centers in the United States.
  
  
  METHODS
  The trials enrolled 27,347 postmenopausal women, aged 50-79 y.
  
  
  METHODS
  We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
  
  
  METHODS
  Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
  
  
  RESULTS
  No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03).
  
  
  CONCLUSIONS
  Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. clk@fhcrc.org
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.forename: Judith
authors.initials: J
authors.lastname: Hsia
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Robinson
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Aragaki
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Alison E
authors.initials: AE
authors.lastname: Baird
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
authors.forename: Shirley A A
authors.initials: SA
authors.lastname: Beresford
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rodriguez