Major problem with this meta-study is the failure to distinguished the HRT, those on Prempro do much worse than the control group, and those on esterfied estrogen plus progesterone did the best (83% reduction with 10 or more years usage).  The trend towards lower dose entail a likely difference in results from earlier studies.  How can they write that in the introductory sentence that“ more than 200 published scientific papers … neuroprotective estrogen is overwhelming” yet fail to find the reasons why more recent studies disagree. The failure to deal with the failure of Prempro & WHI study and of the lower doses now used makes me believe that they have significant ties to the pharmaceutical industry; for this reason I just included a few interesting tibits--jk.  

Thieme ejournal at https://www.thieme-connect.com/DOI/DOI?10.1055/s-0029-1216280 Semin Reprod Med 2009; 27(3): 275-282, DOI: 10.1055/s-0029-1216280

Elizabeth Barrett-Connor^1,3, Gail A. Laughlin^2,

¹ Distinguished Professor, Chief Division of Epidemiology, University of California, San Diego School of Medicine, La Jolla, California

² Assistant Professor, Chief Division of Epidemiology,

³Departments of Family and Preventive Medicine and Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0607;

Email: ebarrettconnor@ucsd.edu; phone: 858.534.0511; fax: 858.534.8625;

Contributor Information.

Abstract

There are more than 200 published scientific papers showing that estrogen has favorable effects on brain tissue and physiology in cell culture and animal models including nonhuman primates. The biological plausibility for a neuroprotective estrogen effect is overwhelming. However, most studies of endogenous estrogen and cognitive decline or dementia fail to show protection, and some suggest harm. Failure to find any consistent association might reflect the limitations of a single time of estrogen assay or poor assay sensitivity. More than half of the observational studies of hormone therapy suggest benefit. Nearly all long term clinical trials fail to show benefit and the longer trials tend to show harm. Failure to adequately adjust for self-selection of healthier and wealthier women and publication bias could account for some, or all, of the protective effect attributed to estrogen in observational studies. Overall, the evidence does not convincingly support the prescription of early or late postmenopausal estrogen therapy to preserve cognitive function or prevent dementia.

Keywords: estrogen, cognitive function, dementia

Introduction

There are more than 200 published scientific papers showing that estrogen has favorable effects on brain tissue and physiology in cell culture and animal models including nonhuman primates. The biological plausibility for a neuroprotective estrogen effect is overwhelming.^{1, 2}

In this paper we review the remarkably less consistent and less convincing evidence for a favorable estrogen effect on preservation of cognitive function and prevention or delay of dementia in postmenopausal women.  {This meta study failed to remove the Prempro users from the group, or even mention the difference--jk.}

Sex differences in cognitive decline and dementia

Women passing through the menopause transition lose about 90% of their premenopausal estrogen level, and typically have blood estrogen levels about one-fourth the usual levels observed in healthy men of the same age. If estrogen is neuroprotective, it might be expected that postmenopausal women would lose cognitive function more rapidly than men, and would have a higher prevalence of dementia than men of similar age.

Evidence for sex differences in cognitive function change and dementia is mixed. This is in part because population-based data comparing the cognitive function decline in men and women are mainly cross-sectional. For example, the Rancho Bernardo Study compared 12 tests of cognitive function in 551 men and 800 postmenopausal women, with women stratified by never, past and current hormone use. In this early study, there was the expected sex difference in cognitive performance, most notably for better verbal test performance (Buschke recall) for women and better visuo-spatial test performance (Trails B) for men. The slope of decline, however, did not differ for men and women, and, among women did not differ by hormone use status.³

Results are similar in prospective studies. In a 10 year population-based Norwegian study of 625 adults, sex differences in eleven cognitive function tests did not change over a 10 year follow-up interval.⁴ In a 6 year follow-up Dutch study of 155 older adults, there was no sex difference in the decline of cognitive function tests.⁵

The prevalence of dementia is said to be higher in older women than in older men, but it is not clear whether this is a true sex difference, or differential survival with fewer men surviving to the ages when dementia is most common, or longer survival of women than men after they develop dementia. As reviewed elsewhere⁶, only 8 of 19 population-based studies of sex differences in dementia published before 2000 tested for statistical significance: four reported a higher prevalence in women and four reported no difference. Of 12 incidence studies, nine included fewer than 20 male cases, and only one study reported a significantly higher incidence among women.

In a study of community-dwelling older adults (aged 65+) from East Boston, who had a detailed clinical neurological examination for dementia, there was no sex difference in the age-adjusted prevalence of dementia (men vs. women odds ratio (OR) = 1.29; 95% confidence interval CI 0.67-2.48), incidence of dementia (OR = 0.92; 95% CI 0.51-1.67), or in the two-fold increased risk of death in participants with prevalent dementia who were followed for 11 years.⁶ The last result is the strongest available evidence that differences in dementia prevalence do not reflect longer survival in women than in men with dementia.

These results contrast with results from a pooled analysis of four European population-based prospective cohort studies of persons aged 65 and older, with 528 incident cases (with excellent clinical diagnosis of dementia type) and 28,765 person years of follow-up.⁷ In this study there was a statistically significant excess of Alzheimer's dementia in women compared to men (adjusted relative risk 1.54; 95% CI 1.21-1.96) but not for vascular dementia (0.72; 95% CI 0.47-1.09).  {VD has a strong causal relation to tobacco, and so this must be adjusted for--jk} The authors note that more men than women aged 80 and older were lost to follow-up (32.2% vs. 26.4%), and that there was an almost doubling of the incidence of Alzheimer's in women between ages 80 and 90, not seen in men. It is therefore possible that the observed sex differences reflect sex differences in survival and loss to follow-up.

Endogenous estrogen

Results from observational studies of endogenous estrogen and cognitive function are inconclusive. Some report harmful associations, some protective, and many fail to identify any clinically meaningful association between serum estrogen levels and cognitive ability.

This may be due, in part, to the difficulty of measuring circulating estradiol in older women. Even the best assay methods (those that extract and separate the estrogens prior to assay) lack sufficient sensitivity to measure estradiol in up to 25% of postmenopausal women. (Measurement of estrone, the primary circulating estrogen after menopause, is less problematic, with 2-4 times higher blood levels than estradiol.) Another source of concern is that most studies are based on single blood samples, not always drawn fasting or in the early morning. While single measurements of most hormones have been shown to reliably characterize average levels over a 2 to 3 year period; estradiol levels are less reproducible.⁸ Finally, about 37% of estradiol in older women circulates bound to SHBG and only the non-SHBG bound fraction (commonly termed bioavailable estradiol) or the free fraction is thought to cross the blood brain barrier.⁹ Given these caveats, the inconsistency of the literature should not be surprising.

In this review, studies of populations (not patients) that include at least 100 women are preferentially reviewed. In the first large population-based study (532 women 65 years or older from the Study of Osteoporotic Fractures women with the highest estrone levels had significantly poorer performance on one (Digit Symbol) of three cognitive function tests at baseline and a greater reduction in scores on another (Trails B) over 5 years compared with women with lower estrone levels.¹⁰ Total estradiol levels were not related to cognitive performance, and neither estrogen predicted performance on the modified Mini-Mental Status Exam (mMMSE), a measure of global cognitive function. These early results did not support the hypothesis that estrogen preserves brain function, however a later report from the Study of Osteoporotic Fractures showed that women with high concentrations of (measured) free and bioavailable estradiol were less likely to develop cognitive impairment (decrease of 3+ points on the mMMSE after 6 years) than women with low concentrations.¹¹ Free and bioavailable estradiol levels were not related to baseline cognitive function test scores in this study.

The Rancho Bernardo Study also failed to identify any consistent cross-sectional association of estrone or total and bioavailable estradiol with performance on 12 cognitive function tests in postmenopausal women.¹² By contrast, a cross-sectional analysis of data from the Rotterdam Scan Study found that women with higher (calculated) bioavailable estradiol levels had significantly poorer memory performance (delayed recall).¹³ Another large cross-sectional Dutch study found the opposite: women in the highest quintile of either estradiol or estrone were 40% less likely to be cognitively impaired (MMSE<27) compared to women in the lowest quintile.¹⁴ There is no obvious reason for these divergent findings of null, harmful, and protective associations. Differences in populations studied, estrogen assays, or cognitive assessment tools are possible explanations, but none seem universal or satisfactory.

Results from case-control studies comparing estrogen levels in women with and without Alzheimer's disease also have been inconsistent; differences were attributed by the authors of a review of 10 such studies to assay sensitivity.¹⁵ Lower levels could reflect lower estrogen levels secondary to the weight loss that often precedes clinical dementia. The Rotterdam study is the only large single-population based study to report whether endogenous estrogens predict future dementia in older non-demented women. Higher levels of total estradiol were associated with an increased 6 year risk of dementia (age-adjusted hazard ratio per standard deviation increase 1.38; 95% CI 1.04-1.84); results were similar for (calculated) bioavailable estradiol. The association seemed to be mainly for vascular dementia.¹⁶ This single study provides no evidence that endogenous estrogen protects against dementia, and raises the possibility of harm.  {Again there was no attempt to remove the bad HRT, Prempro, from the studies--jk.}

Enough of bad work.  This is not atypical.  I found on searching the literature article after article which failed to address the Prempro issue, that what formula of HRT used makes all the difference.   

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