Context Observational studies have suggested that postmenopausal hormone treatment
may improve cognitive function, but data from randomized clinical trials have
been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS)
is an ancillary study of the Women's Health Initiative (WHI) hormone therapy
trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial
was discontinued because of certain increased health risks for women.
Objective To determine whether estrogen plus progestin therapy protects global
cognitive function in older postmenopausal women.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled clinical trial, WHIMS
is an ancillary study of geographically diverse, community-dwelling women
aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen
plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal
women aged 65 years or older and free of probable dementia at baseline, 4532
(92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A
total of 4381 participants (96.7%) provided at least 1 valid cognitive function
score between June 1995 and July 8, 2002.
Interventions Participants received either 1 daily tablet containing 0.625 mg of conjugated
equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching
placebo (n = 2236).
Main Outcome Measure Global cognitive function measured annually with the Modified Mini-Mental
State Examination.
Results The Modified Mini-Mental State Examination mean total scores in both
groups increased slightly over time (mean follow-up of 4.2 years). Women in
the estrogen plus progestin group had smaller average increases in total scores
compared with women receiving placebo (P = .03),
but these differences were not clinically important. Removing women by censoring
them after adjudicated dementia, mild cognitive impairment, or stroke, and
nonadherence to study protocol, did not alter the findings. Prior hormone
therapy use and duration of prior use did not affect the interpretation of
the results, nor did timing of prior hormone therapy initiation with respect
to the final menstrual period. More women in the estrogen plus progestin group
had a substantial and clinically important decline (≥2 SDs) in Modified
Mini-Mental State Examination total score (6.7%) compared with the placebo
group (4.8%) (P = .008).
Conclusions Among postmenopausal women aged 65 years or older, estrogen plus progestin
did not improve cognitive function when compared with placebo. While most
women receiving estrogen plus progestin did not experience clinically relevant
adverse effects on cognition compared with placebo, a small increased risk
of clinically meaningful cognitive decline occurred in the estrogen plus progestin
group.