By Jeffrey T. Jensen, MD, MPH, Editor

SYNOPSIS: Longer lifetime exposure to endogenous estrogen and menopausal estrogen replacement were associated with better cognitive status in older adult women. Women who initiated estrogen therapy early (within five years of the onset of menopause) showed higher cognitive test scores than those who started later.

SOURCE: Matyi JM, Rattinger GB, Schwartz S, et al. Lifetime estrogen exposure and cognition in late life: The Cache County Study. Menopause 2019;26:1366-1374.

Several animal models and in vitro studies support a role for estrogen in memory.¹ Case control and other epidemiologic observational studies generally support a decrease in the risk of Alzheimer’s disease (AD) associated with long duration use of postmenopausal hormone replacement therapy (HT).² However, the large prospective, randomized Women’s Health Initiative (WHI) Memory Study found an increased risk of dementia and cognitive decline associated with oral conjugated equine estrogens (CEE) alone or in combination with medroxyprogesterone acetate (MPA).³

Matyi and colleagues used data from the Cache County Study on Memory in Aging (CCSMA) to study lifetime estrogen exposure and the risk of cognitive decline. The CCSMA surveyed residents of Cache County, Utah, age 65 years or older, without dementia, beginning in 1995. Researchers collected demographic information, including age, education, lifestyle factors (physical activity, smoking, and drinking), diet, and family history. They performed genotyping for apolipoprotein E (APOE) and cognitive and dementia screening. Reproductive health questions included age at menarche and menopause, number of pregnancies and live births, breastfeeding duration, and use of hormonal therapy. The authors used the 100-point modified Mini-Mental State Examination (3MS) to assess the outcome of dementia. To assess exposure to estrogen, they calculated lifetime: 1) endogenous estrogen exposure (EEE) as the reproductive window (menopausal age minus age of menarche), minus total duration of breastfeeding; and 2) exogenous estrogen exposure as the duration of hormone therapy used, type (none, estrogen only, estrogen/progestogen), and timing (no HT; within one year of menopause; between one and five years; six years or more).

To evaluate the relationship between estrogen exposure and 3MS score, the researchers created a series of linear mixed effects models and adjusted the results for additional covariates of interest guided by prior studies, including age, level of formal education, APOE genotype (number of E4 alleles), body mass index (BMI), physical activity, overall health, and depression status. The first model examined only EEE; the second model examined EEE and duration of exogenous HT exposure (time varying); the third model examined EEE and type of HT (none, unopposed, opposed); and the fourth model examined EEE and timing of HT initiation relative to menopause. They also evaluated the effects of HT discontinuation.

A total of 2,147 women without dementia at the baseline visit comprised the study cohort for this paper. The women in the overall study sample had a mean age of 75 years and an average of almost 13 years of education. Almost all of the women were white and Mormon. The mean EEE was 33 years. Participants who reported ever using HT at baseline were significantly younger and better educated, and more physically active than never-users, and had higher baseline 3MS scores.

In the analysis evaluating the effect of EEE on cognition, the unadjusted model found that each additional year of EEE was associated with a 0.05-point higher score on the 3MS (P = 0.008). However, this result did not remain statistically significant in the fully adjusted mixed model. The researchers found a similar effect with respect to hormone therapy duration (each additional year was associated with a 0.02-point higher score). Both combined and estrogen-only therapies increased the 3MS scores. However, none of these relationships remained statistically significant after full adjustment.

All of the women who reported use of HT had higher 3MS scores than nonusers. However, in the fully adjusted model, women who used estrogen continuously or within five years of menopause scored significantly higher than those who initiated HT six or more years after menopause.

COMMENTARY

This study provides some additional evidence that menopausal hormone therapy may reduce the risk of cognitive decline. The results must be viewed with caution, as they represent a highly selected sample of older white women living in Utah. All of the effects are modest, and many of the outcomes lose statistical significance with adjustment. Despite those limitations, the results provide additional support for the timing hypothesis, and add to the body of work that refutes the WHI evidence suggesting cognitive risks associated with hormone therapy.

The Cache County study began in 1995. Zandi and colleagues published the first results from this cohort in the Journal of the American Medical Association in 2002.² I suspect most of you have seen the figures from this publication that show a dramatic difference between men and women in the risk of AD. The risk for women sharply increases beginning around age 80. Zandi and colleagues found a dose response for a reduction in the risk of AD associated with the duration of HT use. The risk associated with greater than 10 years of HT use approached the baseline risk observed in men. While these observations are consistent with the biologic mechanism of estrogen-induced synaptic connections, limitations of the Cache County study design deserve mention. The biggest concern is the healthy user effect. Women using HT had better 3MS scores at baseline, and as health declines (including mental health), many women may discontinue HT. Another problem is the effect of the WHI results in 2002 that led to a tremendous overall decline in HT use in the cohort.

Given that these limitations also apply to the new study by Matyi et al, how should clinicians use this information in counseling? The most interesting new results include the protective effect of EEE on cognitive decline. A late menopause is good for cognitive health, and early menopause is bad. Women who undergo premature ovarian failure or surgical menopause at a young age are at high risk for cognitive decline. I worry about these women, particularly if they receive care from a primary care clinician stuck in the post-WHI mindset of recommending HT at the “lowest dose” and for the “shortest duration.” The Matyi paper also supports that early initiation of HT may result in the best protection.

While attractive, randomized trials have not confirmed the “timing hypothesis.” The Elite-Cog⁴ and KEEPS-Cog⁵ studies explored the hypothesis of a critical window for HT initiation and found no treatment-related benefit of HT with respect to overall cognitive function. Although the outcome of these studies did not support the use of estrogen therapy to prevent subtle cognitive decline in postmenopausal women, this does not rule out a potential protective effect on the subsequent development of AD. In 2017, Finnish investigators published results from the Kuopio Osteoporosis Risk Factor and Prevention cohort, a population-based cohort followed for 20 years. They reported that a history of HT use did not change the risk of AD, but that a trend toward protection emerged with longer duration of self-reported use, with an approximately 50% reduction in risk seen in women reporting greater than 10 years of HT.⁶ To restate, the consistent finding from both the Cache County and the Kuopio studies is that duration of treatment seems to matter for prevention of AD. At least 10 years of use represents an important goal of therapy. Current use of shorter duration may not reduce risk.

While most women remain interested in cognitive benefits, these are not approved indications for HT. Clinicians should always discuss the limitations of the data and the potential risks and benefits of treatment. However, I do not believe that HT increases the risk of dementia. While estrogen is not a panacea for age-related memory loss, a reduction in risk of AD development in women using HT for at least 10 years may come to pass as a hidden additional benefit.

REFERENCES

1. 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.
2. 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.
3. Craig MC, Maki PM, Murphy DGM. The Women's Health Initiative Memory Study: Findings and implications for treatment. Lancet Neurol 2005;4:190-194.
4. 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.
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. Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology 2017;88:1062-1068.