Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial

JAMA. 2003 May 28;289(20):2673-84. doi: 10.1001/jama.289.20.2673.


Context: The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group.

Objective: To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers.

Design: Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls.

Interventions: Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).

Main outcome measures: Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists.

Results: One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk.

Conclusions: Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Biomarkers / blood
  • Double-Blind Method
  • Estrogen Replacement Therapy* / adverse effects
  • Estrogens, Conjugated (USP) / adverse effects
  • Estrogens, Conjugated (USP) / therapeutic use*
  • Female
  • Humans
  • Medroxyprogesterone Acetate / adverse effects
  • Medroxyprogesterone Acetate / therapeutic use*
  • Middle Aged
  • Postmenopause
  • Progesterone Congeners / adverse effects
  • Progesterone Congeners / therapeutic use*
  • Proportional Hazards Models
  • Risk Factors
  • Stroke / chemically induced
  • Stroke / classification
  • Stroke / epidemiology*
  • Survival Analysis


  • Biomarkers
  • Estrogens, Conjugated (USP)
  • Progesterone Congeners
  • Medroxyprogesterone Acetate