Is there a window of opportunity for using estrogen to benefit the brain?

Issue: March 2017

Click here to read the Cover Story, "Menopausal hot flashes pose risks beyond discomfort."

Evidence for a critical window is unclear.

When it comes to a critical window a key question is: When might that window open, and when might it close? It seems reasonable that the window might open at the point in the menopausal transition when memory performance begins to decline. Longitudinal studies show that memory begins to decline as early as the late reproductive stage and appears to rebound during the postmenopausal stage. Critically, these declines in memory persist after controlling for menopausal symptoms. Advancing age cannot explain declines in memory during the menopausal transition because the declines persist after controlling for age, and memory appears to rebound during the postmenopausal stage despite advancing age. These studies, therefore, suggest that the window might begin to open early in the menopausal transition and begin to close during the postmenopausal years.

Let’s consider then the clinical trials of hormone therapy during that window. Three high-quality, randomized controlled trials, including one from the Women’s Health Initiative, showed neutral effects of HT on memory and cognition in younger postmenopausal women. A reasonable conclusion from those trials is that, while HT might be safer for cognitive function when given early in the postmenopausal period than when given later, there is no evidence of a critical window for cognitive benefit during that time. What about earlier on in the transition? Unfortunately, we have very little data from randomized clinical trials and critical questions remain unanswered, including: “How does use of HT or oral contraceptives in the perimenopause — as distinct from the early postmenopause — affect cognition?” “Does HT affect cognition in women with moderate to severe vasomotor symptoms (the very women for whom HT is indicated)?” “Does early use of HT have effects on Alzheimer’s disease risk and the neuropathology underlying risk?”

Given that two-thirds of Alzheimer’s disease patients are women, it is particularly important to identify factors that modify memory and the risk for Alzheimer’s disease in this population. It is now widely accepted that to prevent Alzheimer’s disease later in life, it is necessary to intervene at midlife. How HT fits into that broad perspective of Alzheimer’s disease is unclear and deserving of further study.

References:
Epperson CN, et al. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2013-1808.
Espeland MA, et al. JAMA Intern Med. 2013;173:1429-1436;doi:10.1001/jamainternmed.2013.7727.
Gleason CE, et al. PLoS Med. 2015; doi:10.1371/journal.pmed.1001833.
Greendale GA, et al. Neurology. 2009;doi:10.1212/WNL.0b013e3181a71193.
Henderson VW, et al. Neurology. 2016;doi:10.1212/WNL.0000000000002980.
Pauline Maki, PhD, is the senior director of research at the Center for Research on Women and Gender and a professor of psychiatry and psychology at the University of Illinois at Chicago. She reports no relevant financial disclosures.

There is no critical window.

The window of opportunity hypothesis suggests that effects of estrogen-containing HT on some health outcomes depend on timing. According to this hypothesis, HT initiated and used by younger women closer to the time of menopause could benefit the brain, but therapy initiated by older women more remote from the time of menopause might harm the brain. Much of the discussion centers on Alzheimer’s disease, the most common cause of dementia, and cognitive aging, which does not involve dementia.

For Alzheimer’s disease, observational research generally suggests that women who use HT are at reduced risk for developing Alzheimer’s disease. Most women who use HT do so for vasomotor symptoms, starting at a relatively young age and then stopping a few years later. Estrogen effects on dementia risk have been examined in only two clinical trials: the WHI Memory Study for women with a uterus (daily treatment with conjugated equine estrogens combined with medroxyprogesterone acetate, or placebo) and the WHI Memory Study for women without a uterus (the same treatment, except that medroxyprogesterone acetate was omitted). Only 108 women in these two trials developed dementia from any cause (results for just Alzheimer’s disease were not published) — 68 in the two estrogen groups and 40 in the two placebo groups. The differences were significant for women with a uterus and in analyses that combined women from both trials.

The critical window hypothesis provides an explanation for different inferences from observational research (estrogens reduce Alzheimer’s risk) and clinical trial research (estrogens increase dementia risk). Another explanation is that women who used HT in observational studies were likely healthier than women who did not, and it was this important difference — and not hormone use — that accounts for the discrepancy. At present, there is no way to resolve this conflict.

For cognitive aging, it is well-known that certain cognitive abilities, such as memory, decline with age. Several large clinical trials have examined whether HT started after menopause affects cognition in the absence of dementia. These trials included women near to, and further from, menopause; and the results were essentially null: no substantial benefit or harm. For cognitively normal, healthy postmenopausal women, there is no convincing evidence for a critical window for cognitive aging.

To sum up, it is uncertain whether there is a critical window for Alzheimer’s risk. There seems to be no critical window for cognitive aging.

Victor W. Henderson, MD, MS, is a professor of health research and policy and of neurology and neurological sciences at Stanford University. He directs the Stanford Alzheimer’s Disease Research Center. He is a past president of the North American Menopause Society. He reports no relevant financial disclosures.