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A Systematic Review of Clinical Trials of Hormone Therapy on Cognitive Function: Effects of Age at Initiation and Progestin Use

Abstract: The putative protective effects of hormone therapy (HT) have been cast in doubt by recent findings from the Women's Health Initiative Memory Study showing an increase in dementia and an increased likelihood of impaired cognitive status in women initiating HT after age 65. To explore the external generalizability of those findings to younger postmenopausal women, the medical literature was surveyed for randomized, double‐blind, placebo‐controlled trials of treatment with either estrogen alone or estrogen plus a progestin on neuropsychological test performance. Findings from trials in younger women (<65 years) are presented separately from those in older women (≥65 years). This review finds little support for beneficial cognitive effects in older women of estrogen alone or in combination with progestin. However, evidence from younger women suggests potential beneficial effects in select cognitive domains, particularly among symptomatic women and recently menopausal women, and scant evidence of harm. There is a dearth of studies of the cognitive effects of estrogen plus progestin in younger women. Future studies systematically exploring the effect of age and progestin use are needed to better characterize the effects of HT on cognition in younger women. Without firm evidence of benefit to younger women, it is prudent to caution early postmenopausal women about the cognitive risks observed in WHI, recognizing the low likelihood of dementia at that age.