Effect of hormone replacement therapy on self-reported cognitive symptoms: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial

OBJECTIVE: To describe self-reported cognitive changes in 875 postmenopausal women aged 45-64 years and assigned randomly to hormone therapy (either estrogen alone or estrogen in combination with a progestin). METHODS: A 3-year placebo-controlled trial which included self-report data on problems with forgetfulness, concentration and distraction in groups of women assigned randomly to placebo, estrogen alone or estrogen plus one of three progestin regimens. RESULTS: Women assigned to any active treatment were consistently less likely to report cognitive symptoms than women assigned to placebo, but these results were not statistically significant. When compared with women assigned to estrogen plus any progestin, women assigned to estrogen alone had a significant increased risk for reporting problems with forgetfulness at follow-up (odds ratio, OR = 1.47). In the absence of problems with distraction at baseline, women assigned to estrogen alone were significantly less likely to report problems with distraction at follow-up, compared to women assigned to estrogen plus any progestin (OR = 0.36). Assignment to a continuous progestin regimen in combination with estrogen was marginally associated with an increased risk for reporting concentration problems at follow-up, compared to cyclic progestin regimens (OR = 1.63). CONCLUSIONS: These results provide some evidence to support the hypothesis that estrogen improves memory, but findings are not statistically significant in this healthy middle-aged cohort. These data suggest that estrogen in combination with any progestin confers a decreased risk for reporting forgetfulness at follow-up, compared to estrogen alone. However, there is evidence that distraction problems reported at follow-up were side-effects of progestin. There is also some evidence that women administered progestins cyclically were at lower risk for reporting cognitive symptoms at follow-up, particularly concentration problems.