Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial

JAMA. 2003 May 28;289(20):2651-62. doi: 10.1001/jama.289.20.2651.


Context: Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy.

Objective: To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo.

Design, setting, and participants: The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS.

Intervention: Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303).

Main outcome measures: Incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment.

Results: The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P =.01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P =.72).

Conclusions: Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.

Publication types

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

MeSH terms

  • Aged
  • Cognition / drug effects*
  • Cognition Disorders / chemically induced
  • Cognition Disorders / diagnosis
  • Cognition Disorders / epidemiology*
  • Dementia / chemically induced
  • Dementia / diagnosis
  • Dementia / epidemiology*
  • 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*
  • Neuropsychological Tests
  • Postmenopause
  • Progesterone Congeners / adverse effects
  • Progesterone Congeners / therapeutic use*
  • Proportional Hazards Models
  • Risk


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