By Jeffrey T. Jensen, MD, MPH, Editor

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; he receives grant/research support from Medicines 360, Agile, and Teva; and is a consultant for MicroChips and Evofem.

SYNOPSIS: Women randomized to receive postmenopausal oral estradiol therapy did not show improved memory, executive function, or global cognition, and timing of initiation of hormonal treatment did not affect the outcome.

SOURCE: Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016;87:699-708.

The Early versus Late Intervention Trial with Estradiol (ELITE) study, a randomized, placebo-controlled, double-blind trial supported by the National Institute on Aging, was designed to test the hypothesis that time of onset of hormone therapy (HT) affects outcomes. Although the primary objective of ELITE was the relationship of HT to cardiovascular health in postmenopausal women, other outcomes were followed. The ELITE-Cog study by Henderson et al presents data on the effects of HT on cognition. The primary hypothesis of this study was that postmenopausal estrogen initiated soon after menopause (< 6 years) would affect verbal memory differently than initiation at a later time ( 10 years).

Conducted at the University of Southern California, the ELITE study recruited healthy (no diabetes or clinical evidence of cardiovascular disease) postmenopausal women. Enrollment was stratified according to the number of years past menopause: < 6 years (early) or 10 years (late). Subjects were randomized to receive oral 17ß-estradiol (1 mg daily) or matching placebo. Women with a uterus received cyclic micronized progesterone as a 4% vaginal gel or matched placebo gel for 10 days each month. The investigators assessed cognitive skills at baseline, 2.5 years, and five years using a comprehensive neuropsychological battery that emphasized standardized tests sensitive to age-related change to assess outcomes.

Out of 643 randomized in ELITE, 567 underwent cognitive assessments at baseline and 2.5 years, and 457 contributed data to the five-year outcome. The overall adherence to the study regimen was excellent (98%). As expected, serum estradiol levels were significantly higher in the active treatment group (median 40 pg/mL [interquartile range 27-58]) compared to placebo (11 [9-14]).

Results of the cognitive tests showed no overall significant or clinically important difference in verbal memory in women who received estradiol compared to placebo, and no difference with respect to early or late initiation of hormonal therapy. A similar lack of effect was seen for executive function and global cognition. The authors concluded that estradiol therapy neither benefits nor harms cognitive ability regardless of time of initiation of therapy after menopause.

COMMENTARY

Forgetfulness and cognitive decline have long been associated with aging. Products promoted to counteract this effect include herbal supplements (Ginkgo biloba), antioxidant vitamin preparations, and other nutraceuticals. Although much greater scientific evidence supports an essential role for estrogen in brain function,1,2 we lack solid clinical data to support this indication for hormonal therapy. Nonetheless, many clinicians recommend hormonal therapy to prevent cognitive decline, and many healthy postmenopausal women not bothered by hot flushing or vaginal symptoms use therapy precisely for this reason. Observational studies documenting a decreased risk of Alzheimer’s dementia provide clinical evidence to support this use.3 However, just as with cardiovascular disease, the randomized Women’s Health Initiative (WHI) study challenged the conclusions of basic science and observational and database research showing brain benefits of estrogens. In the subset of women aged 65 years or older in the WHI study, HT did not improve cognitive function when compared with placebo, and more women in the HT group experienced cognitive decline.4 Just as with cardiovascular disease, one explanation for the negative effects observed in WHI and the positive benefits seen in observational studies may be a critical window for initiation of treatment. The randomized ELITE-Cog study was designed to evaluate this “Aging” or “Timing” hypothesis with respect to cognitive outcomes.

The findings of no difference in verbal memory or an overall cognitive benefit of estradiol treatment in the ELITE-Cog, while disappointing to advocates of hormonal therapy, demonstrate the value of doing the experiment. Living in a fact-based rather than faith-based reality requires courage. Participation in science means exposing a beautiful hypothesis to the risks of experimental validation. The fact that most hypotheses are proved wrong does not undermine the process. A vigorous debate brings us closer to the truth, and our patients need our help to distinguish between what is suspected, confirmed, and refuted by solid clinical experiments. We also must communicate the limitations of data and the areas of future study. Facts matter, and they guide us to re-formulate hypotheses and bring us closer to the truth. The conservative approach is to accept, and act within, scientific consensus while searching for alternative explanations. The data from ELITE-Cog refute the timing hypothesis that early initiation of estradiol therapy within six years of the onset of menopause will improve verbal memory and cognitive function.

The results of ELITE-Cog are consistent with KEEPS-Cog.5 The KEEPS study randomized recently postmenopausal women to receive transdermal estradiol or oral conjugated equine estrogens (with cyclic micronized progesterone in women with a uterus). Like the ELITE study, the parent KEEPS study looked at cardiovascular outcomes, and KEEPS-Cog evaluated cognitive outcomes. Participants averaged 53 years of age, and were 1.4 years past their last menstrual period. As with ELITE-Cog, no treatment-related benefit of HT was seen with respect to cognitive function.

Taken together, these results do not support use of estrogen therapy to prevent cognitive decline in postmenopausal women. However, research should continue in this field. Some brain researchers believe that susceptibility for irreversible cognitive effects may manifest in the perimenopausal transition.6 Would even earlier initiation of therapy improve outcomes? Others suggest a “Goldilocks” effect for estrogen therapy; too little gives no benefit, too much harm (e.g., increased thrombosis risk).7 Perhaps the estrogen exposure in both ELITE-Cog and KEEPS-Cog was insufficient for benefit? The median estradiol levels on treatment were around 40 pg/mL. As I have previously noted, one result of the WHI has been a consistent pressure to find the “lowest effective dose” of estrogen. While levels of estradiol around 40 pg/mL are considered bone protective, this may be insufficient to produce cardiovascular or brain benefits. I am not a fan of the minimum dose approach that has been advanced by many following the WHI. Keeping serum estradiol in the normal mid-follicular cycle range of 50-80 pg/mL seems more appropriate. Prescribing estradiol allows you to check a level to assist with management of patients. Finally, the timeline for assessment of outcomes may have been too short to demonstrate a benefit. In Cache County, only use of HT for more than 10 years provided maximal protection from Alzheimer’s disease.3

However, all of these are hypotheses, and we need to deal with facts, not faith. While we wait for more evidence, we should communicate to our patients that the evidence is insufficient to recommend the use of postmenopausal HT solely for cognitive benefit.

REFERENCES

  1. Rettberg JR, Yao J, Brinton RD. Estrogen: A master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 2014;35:8-30.
  2. McEwen BS, Akama KT, Spencer-Segal JL, et al. Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms. Behav Neurosci 2012;126:4-16.
  3. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: The Cache County Study. JAMA 2002;288:2123-2129.
  4. Rapp SR, Legault C, Henderson VW, et al. Subtypes of mild cognitive impairment in older postmenopausal women: The Women’s Health Initiative Memory Study. Alzheimer Dis Assoc Disord 2010;24:248-255.
  5. Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015;12:e1001833.
  6. Brinton RD, Yao J, Yin F, et al. Perimenopause as a neurological transition state. Nat Rev Endocrinol 2015;11:393-405.
  7. Koebele SV, Bimonte-Nelson HA. Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it? Horm Behav 2015;74:86-104.