HT Does Not Affect Cognition in Younger WHI Women
Pauline M. Maki, PhD
Summary
Espeland MA, Shumaker SA, Leng I, et al; for the WHIMSY Study Group. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med. 2013 June 24. [Epub ahead of print] Level of evidence: II-1.
Researchers examined the effect of conjugated equine estrogens (CEEs) on cognitive function when initiated in postmenopausal women aged 50 to 55 years. The study population of 1,326 women from the Women's Health Initiative (WHI) trials (using 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate [MPA] over a mean of 7.0 years) was assessed for cognitive function with telephone-administered tests measuring global and domain-specific cognition. Testing occurred after an average of 7.2 years, when the women were a mean of 67.2 years old, and was repeated 1 year afterwards.
Primary outcome was global cognitive function, and secondary outcomes were verbal memory, attention, executive function, verbal fluency, and working memory. Results were similar among women assigned to CEE and women assigned to placebo. No overall differences were found for any cognitive domain. CEE produced neither benefit nor risk to cognitive function.
Commentary by Pauline M. Maki, PhD.
The critical window hypothesis has been proposed to explain apparently discrepant findings regarding the impact of hormone therapy (HT) on memory and risk for Alzheimer's disease.[1] Meta-analyses of observational studies revealed a significant 29% decreased risk of Alzheimer's disease in women who used HT.[2] In contrast, the WHI Memory Study (WHIMS) revealed a doubling of the risk of all-cause dementia in older women (mean age, 72 years) randomized to receive CEE/MPA and no increased or decreased risk of all-cause dementia in women randomized to receive CEE alone.[3,4] The discrepancy between the observational studies and WHIMS has been attributed to differences in the timing of treatment initiation, with younger age at initiation (around the time of the final menstrual period) in the observational studies versus a much older age in WHIMS.
To date, all observational cohort studies that specifically examined the timing of HT initiation on the risk for Alzheimer's disease have provided support for the timing hypothesis.[5-7] Now an ancillary study, the WHIMS of Younger Women (WHIMSY), reveals no impact of either CEE or CEE/MPA on a measure of global cognitive function or other cognitive outcomes. Those data were interpreted as suggesting that treatments may be safer when initiated at a younger age.
As acknowledged by the authors, WHIMSY does not address whether initiating hormone therapy during menopause and maintaining therapy until symptoms pass affects cognitive function, either in the short or longer term. The average years since final menstrual period in the CEE group at the time of randomization was 9 years, but the average time since menopause is unclear since roughly 40% of women in the WHI had bilateral oophorectomy. Although WHIMSY suggests no benefit from CEE/MPA even with early treatment initiation, this is not surprising in light of evidence that CEE/MPA actually can have a small negative impact on verbal memory even when given to healthy early postmenopausal women.[8,9]
The current findings raise the reassuring possibility that any negative impact of early use CEE/MPA may not be sustained. Critical and unanswered questions are: 1) whether other combination estrogen/progestogen treatments may confer cognitive benefits; and 2) whether estrogen alone confers benefits when used in the critical window.
