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Women, estrogen, cognition, and Alzheimer's disease.

Converging evidence over almost 2 decades has built a strong case for 17 beta-estradiol (estradiol, E2) as protective of the postmenopausal female brain. Multiple investigations and meta-analysis, including basic science and observational and clinical studies, strongly suggest significant benefits to cognitive function and decreased risk of dementia for women on estradiol, especially with transdermal delivery. Conjugated equine estrogens (GE), on the other hand, may negatively affect cognitive function or confer no benefit, and may increase the risk of dementia in women over 65. lt is imperative that clinicians be aware of this substantial data so that we can educate our patients, and the general public, about the significant protective benefit of estradiol and offer the best possible options for maintenance of cognitive health.

Women do not arrive at the menopausal transition with equal health status or equal risk of Alzheimer's disease or any other age-related disorder. As is always the case, each woman must be considered unique, and an in-depth history, physical exam, and laboratory analysis will need to be completed in order to make optimal health recommendations.

Conjugated Equine Estrogens

CEE, derived from the urine of pregnant mares (Premarin and Prempro), was approved by the FDA in 1942 and is the primary form of postmenopausal estrogen replacement used in the US. CEE consists of 50% to 70% estrone and 22% to 32% equilin and 7 or more other poorly characterized estrogens, not found in the human female. (1) Prior to menopause, the major estrogen is ovarian produced estradiol, a very potent estrogen, with a high density of receptors in the brain. More recently, some clinicians and their patients are shifting to the use of topical estradiol, and many products are now available, including estradiol patches, gels, and creams. The advantages of this form of estrogen compared with oral equine estrogens are well demonstrated but seldom discussed clearly in the public forum. This will be addressed after a brief review of the epidemiology of Alzheimer's disease.

Alzheimer's Disease

A large upsurge in Alzheimer's disease (AD) is expected with the continuing demographic shift to a much more elderly population. Incidence rates for AD are predicted to increase from 4.5 million in 2000 to 13.2 million in 2050 as Baby Boomers age. (2) Female gender is significantly related to increased incidence of AD, and women are at greater risk of developing AD with an estimated odds ratio of 1.56. (3) Women currently make up 68 I of those with AD, and that group is estimated to be between 5% and 10% of the total current population of the US. (4)

Epidemiologic studies estimate that if it were possible to increase cognitive reserve by 5%, that effect would decrease AD by one-third. (5) Interventions that substantially diminish AD incidence in women would clearly result in significant quality of life enhancement and have enormously beneficial social and economic impact.

There is increasing evidence that the pathology of AD starts decades before the onset of the clinical symptoms. Once the symptoms of dementia appear, significant neuronal loss has already occurred and disease progression is inevitable. The time for early detection and intervention is the beginning of the asymptomatic period of neurologic damage, rather than years later at the onset of symptomatic dementia. Though research has not identified exactly when brain deterioration begins, there is compelling evidence that the steep drop in estrogen levels during the menopausal transition is closely linked to an increased risk of cognitive decline and subsequent dementia in women. (6), (7) Thus beginning estradiol during the menopausal transition is likely to delay the onset of dementia, and may prevent AD in many women.

Basic Science Weighs In

In basic science research, animal and in vitro studies demonstrate multiple mechanisms for beneficial estrogen action in the brain. Estrogens have been found to be associated with the maintenance and protection of brain structures; hence it is biologically plausible that maintaining high levels of estrogens in postmenopausal women could protect against cognitive decline. Research, as detailed below, supports the rationale for these positive effects and provides insight into the mechanisms of estradiol in the brain.

Estrogen receptors (ER) are found in selective areas of the brain, including the hippocampal areas, amygdala, basal forebrain, pituitary, and hypothalamus. The hippocampal and amygdala areas, along with the basal forebrain, which are strongly associated with memory and mood, are also areas selectively affected by neurodegeneration in AD. (8-12) Estrogen increases the density of pyramidal hippocampal neurons, and increases synaptic plasticity in the hippocampus via activation of estrogen receptors. (13-15)

Cumulative evidence supports a facilitative role for estrogen on the major neurotransmitter systems in the brain. (16), (17) Neurotransmitters influenced by estrogen include acetylcholine, serotonin, dopamine, and norepinephrine, and all of these are involved in the cognitive functions affected in AD. (18) The cholinergic system is involved in attention, learning, and memory. The primary site for the cholinergic system is the basal forebrain, an area with early pathologic changes in AD. Basic science demonstrates that estrogen enhances the action of the cholinergic system. (19-25) Therefore, the sharp fall in estrogen at the time of menopause could contribute to a decline in the cholinergic system and result in cognitive loss and predispose to AD. Estrogen has favorably affected brain dopamine, norepinephrine, and serotonin activity in multiple studies. (26-30)

In other research, estradiol protected the brain from injury, including stroke, lipid peroxidation, oxidative damage, and beta amyliod toxicity. (31-35) Amyloid beta (AB) plaque deposition is one of the hallmarks of AD. Many animal model studies suggest that estrogen reduces AB levels and estrogen deficiency accelerates AB plaque formation.36 Studies also show that estrogen increases clearance of insoluble AB from CSF. (34), (37) Estrogen has been shown to reduce inflammatory response to AB and to protect against AB-mediated toxicity. (34), (35), (37), (38) Given this widely acknowledged relationship between estrogen, AB, and AD, the likelihood is high that the sharp drop in estrogen at menopause contributes to detrimental cognitive effects and increases the risk of AD.

Estrogen demonstrates beneficial impact on cerebral blood flow. Estrogen receptors are found in both cerebrovascular smooth muscle and endothelial layer cerebral cells. Increased dilation of vessels and improved cerebral flow appear to be mediated by estradiol's effect on vasoregulators such as nitric oxide and prostanoids. (37), (38) Significantly, estrogen's effects on nitric oxide production occur in the hippocampus and forebrain, areas of degeneration in AD. (39), (40) Cerebral blood flow is favorably affected by estrogen's ability to increase mitochondrial energy production. (41-44) Reactive oxygen species and peroxides, the harmful byproducts of mitochondrial energy production, are less damaging in the presence of estrogen. (42) The neuroprotective actions of E2 appear to be mediated through both the classic genomic and more rapid cell membrane receptor mechanisms, and are expressed via both estrogen receptor alpha (ER[alpha]) and estrogen receptor beta (ER[beta]) subtypes. (45-50) This evidence further strengthens the plausibility of the beneficial and protective impact of estrogen on cognition and AD.

CEE versus Estradiol

Although the basic science studies make a very strong case for the advantages of estrogen replacement at menopause, the results of observational and clinical studies of estrogen and progestin therapy in postmenopausal women are more mixed. Basic science extensively characterized the neurological effects of estradiol, and almost no studies of the effects of estrone or CEE have been performed. The differing neurobiology of estradiol versus CEE may be a major factor in these conflicting results. Sixteen observational studies have been published over the last 20 years to evaluate the effect of postmenopausal hormone therapy on the risk of dementia. The majority of these studies evaluated the impact of CEE, the hormone replacement most used in the US; however, some estradiol studies were included. Four meta-analyses from the above observational studies concluded that there was a significant reduction in the risk of developing dementia in the group of women who currently used or had used hormone therapy. (51-54) Importantly, the above meta studies concluded that the neuroprotective effect from estradiol treatment was more substantial than that with CEE, and that the addition of medroxyprogesterone (Provera) as the progestin was detrimental.

In an excellent 2009 review article, the University of Wisconsin group summarizes the clinical studies of the last 17 years, comparing the cognitive impact of estradiol versus CEE in menopausal women. (55) Fifteen of 20 estradiol studies show cognitive benefit, 5 of 20 show no benefit. None show harm. Only 6 of 14 CEE studies show cognitive benefit, 8 of 14 show no benefit. However 2 of the 8 "no benefit" CEE studies show harmful cognitive effects. Both harmful results were from the Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, and we will review the important differences in these studies below. (56), (57) It is important to point out that the majority, but not all, of the estradiol studies used transdermal estradiol, and topical application of estradiol may improve clinical outcomes, whereas the CEE was always administered orally. Hence age, route of delivery, type of estrogen, progestin use, and progestin type are probably all critical pieces of the puzzle. The overwhelming weight of evidence in the clinical trials supports improved cognition and lower AD risk with estradiol use, but is inconclusive regarding CEE use.

Medroxyprogesterone

The WHIMS, a substudy group of the very influential 2002 Women's Health Initiative Study (WHI), found an increased risk for mild cognitive impairment and dementia in postmenopausal women 65 years and older, treated with equine estrogens and the synthetic progestin medroxyprogesterone (MPA). (58-61) An updated report in 2009 by Resnick et at of the WHIMS CEE alone (no MPA) arm of the study showed no harmful effect of verbal memory over time and no increased risk of AD. This implicates the addition of MPA as a causal factor in the deleterious results. (62), (63) A possible mechanism for this effect is elucidated in a 2011 study showing that medroxyprogesterone acetate antagonizes estrogen upregulation of brain mitochondrial function. (64) Space does not allow a full discussion of progesterone and progestin impact on neurocognition.

A new study from Stanford high lights important differences between estradiol and CEE in cognitive effects. (65) Sixty-eight women, aged 49 to 68 with at least one risk factor for AD, on either estradiol or CEE were included in the study. Each woman underwent an extensive battery of neuropsychological testing, to differentiate as precisely as possible her cognitive abilities. Women receiving estradiol showed significantly better verbal memory performance compared with women on CEE regardless of age, years of education, IQ scores, risk factors for AD, including APOE4, duration of endogenous and exogenous estrogen exposure, or concurrent progesterone use. After controlling for menopause-related variables such as length of endogenous and exogenous estrogen exposure, results also showed significantly better attention, working memory, processing speed, and executive function performance among women receiving estradiol. Declines in verbal memory are thought to be one of the early signs of AD, particularly when delayed word list and story recall measures are combined as in this important study. (66), (67)

What accounts for the difference between estradiol studies and CEE in clinical studies? CEE contains primarily estrone. As previously noted, human brain tissue is rich in estradiol receptors, and the most abundant premenopausal estrogen is estradiol. At menopause, however, levels of estradiol decrease precipitously to approximately 1/10 of those found in menstruating women, whereas levels of estrone decline to a lesser extent. (68) To enhance the estradiol cognitive receptor actions in brain tissue, and to more closely mimic the premenopausal brain state, estradiol appears the better choice.

Transdermal Estradiol

Research suggests that transdermal estradiol offers advantages over oral estradiol or CEE. The transdermal delivery avoids the deleterious impact of hepatic first pass, including increased estrone to estradiol level, lower estradiol level, and increased inflammatory and procoagulation markers. Women on oral estrogen, either CEE or estradiol, increase their CRP levels, while women on topical estradiol do not. (69-71) Elevated CRP is also associated with increased risk of Alzheimer's disease and cerebrovascular dementia, which often co-occur. (72), (73) Topical estradiol lowers fibrinogen, a coagulation marker, and oral estradiol does not. (74) Oral estradiol raises procoagualtion effects by increasing prothrombin activation peptide, increasing F1 and F2, decreasing activity of antithrombin, and lowering plasminogen, while transdermal estradiol has no procoagulation effects. (74) In a UK observational study with over 15,700 cases and 59,900 controls, there was no increased stroke risk with transdermal E2 treatment at a dose of 50 micrograms per day or less as there was with oral estrogen. (75) Higher plasma levels of estradiol are associated with transdermal estradiol use, and higher levels of estradiol correlate with better neurological health in postmenopausal women. (76), (77) Gleason found better verbal memory in middle-aged women with a parental history of AD (carriers of APOE4 were limited) who were using opposed topical estradiol compared with those using opposed CEE or who had never used hormone therapy. The no-hormone group also outperformed the CEE group. (78) Joffe et al. demonstrated a significant positive brain effect in their fMRI study of 35 recently postmenopausal women after topical E2 compared with 35 controls using topical placebo. Measures of fMRI activation showed increases in the frontal cortex during tests of verbal and spatial memory after topical estradiol use but not after placebo. Joffe et al. concluded that working memory and executive function, residing in frontal cortex, were improved with transdermal estradiol. (79)

Healthy Cell Bias

Some researchers critical of WHIMS have argued that it was not a prevention study because the participants, all 65 years or older, were beyond the age of primary prevention. (80) Critics argue that a study with women at the onset of menopause may have yielded more positive results, and from this has evolved the "healthy neuron bias" theory. Because of the unexpected negative effects of combined Premarin and Provera on cognition and AD risk in women over 65, many researchers have taken a critical look at the study. Healthy neuron proponents suggest that early menopausal women have healthy neurons, and when exposed to estrogen, maintenance and protection of the brain cells results. In older women, further from menopause, neuronal architecture has undergone degenerative changes, and when exposed to estrogen at this time, a further degenerative effect ensues. (80), (81) Several studies show increased hippocampal volume in postmenopausal women only if they began estrogen within a limited window of time, close to cessation of menses. (82), (83) Short-term treatment with higher levels of estradiol (1 mg per day, then 2 mg per day) compared with placebo partially blocked an anticholenergic drug-induced challenge to verbal memory in younger women, aged 50 to 62, but further impaired verbal memory with this drug in older women, aged 70 to 81.84 Basic science suggests mechanisms by which the response to estrogen is less favorable if treatment is initiated following long-term ovarian hormone deprivation. (85)

Topical Estradiol for AD?

While the critical timing theory of early initiation of estrogen has strong support in the literature, and basic science tells us that early estrogen replacement has more neurocognitive benefit, some studies suggest that estradiol may continue to have benefit even in older women diagnosed with AD. In 2 randomized trials, Asthana et al. found improvement in cognition in women with dementia with a 0.1 transdermal estradiol patch. (86) A second placebo-controlled, double-blind study shows positive cognitive response to transdermal estradiol in women with AD. (87) The type of estrogen, estradiol, and the topical route of administration, as opposed to the oral route, may be critical factors in the beneficial dementia results above.

Symptomatic or Not

In their 2001 meta-analysis, Le Blanc et al. noted differences in results in women who were symptomatic compared with those who were not. (53) Women with vasomotor symptoms; that is, hot flashes and/or night sweats, treated with estrogen had significant improvement in verbal memory, vigilance, reasoning, and motor speed. Women who were asymptomatic had no benefit. Possibly postmenopausal women without these or other low estrogen symptoms have higher estradiol levels; therefore, they accrue no additional benefit from replacement of estrogen. A 2012 study finds better semantic memory in midlife postmenopausal women with higher total and free endogenous estradiol levels. No association was found with estrone levels. (88) In the KEEPS (Kronos Early Estrogen Prevention Study), currently in progress, the initial evaluation found a significant association between higher estradiol levels and improved performance on the mini-mental status exam. (89) This supports the importance of a careful evaluation by the clinician to assess the need for estrogen replacement including estradiol levels.

What Now?

More studies will undoubtedly be needed in this area as the population of aging women continues to increase. More and more women are living longer, and unfortunately the number with Alzheimer's increases with each year of age. (90), (91) The KEEPS and KEEPS C/A (KEEPS cognitive and affective study) are large-scale longitudinal studies with transdermal estradiol as one of the major hormone variables. KEEPS is due to report out in 2013. Potentially, these results will help answer many pressing questions on the risks and benefits of hormone replacement.

There is no formulaic protocol for assessing the need for estradiol replacement. In my 17 years of helping women make this decision, the most frequent concerns at the time of menopause are vasomotor symptoms, especially if they result in loss of sleep; mood issues; and cognitive loss, including word-finding, learning, and memory. In my experience, if a woman's serum estradiol level is below 25 pg/ml (and it is often below 10 pg/ml), the above symptoms will improve with topical estradiol; however, dosage must be individualized.

Conclusion

Because many women will live half of their lives after menopause, it is crucial that decisions made at the time of menopause, with cognitive and other long-term health consequences, are carefully considered. A menopausal woman, with the guidance of her healthcare provider, has a complex decision to make regarding hormone replacement. The risk of osteoporosis, cardiovascular disease, and breast, uterine, and ovarian cancer, along with dementia risk must be weighed. Here only the cognitive and dementia-related issues are addressed due to limited space. For clinicians, consideration of all variables is a time-consuming process, and each woman needs an in-depth consultation taking into account her family history, personal medical history, risk factors, symptoms, and concerns. A laboratory analysis will help guide this decision. A diet high in vegetables; adequate in high-quality protein and fat; and low in sugar, trans fats, alcohol, and processed foods is advantageous. Evidence suggests that lifestyle factors such as physical activity, lower exposure to stress, and toxin avoidance improve outcomes.

Even with the ideal consultation with a well-informed practitioner, there are not always clear-cut answers because the data are inconclusive. However, the preponderance of evidence supports the beneficial effects of transdermal estradiol on cognition and the protective effects regarding Alzheimer's disease. We await the KEEPS, KEEPS C/A, and other studies to help us understand how to optimize cognitive and other health factors for women both at the time of the menopausal transition and throughout the many years that follow.

Notes

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Ann Hathaway has practiced functional and integrative medicine since 1997 in San Rafael, California. The menopausal transition is one of her areas of special interest. She is a member of the institute for Functional Medicine and a director of the Orthomolecular Health Medicine Society. She was board certified in family practice medicine in 1983, and was assistant professor of family practice medicine, UC Davis Medical School, from 1983 to 1986. She then served in the Marin County Public Health Department for 20 years, caring for tuberculosis and STD patients, and managing indigent medical problems. Over those years she began to study functional and integrative medicine and developed her own private practice utilizing her new training.

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Dr. Hathaway graduated summa cum laude from the University of California Berkeley in 1975, the University of California Medical School in San Francisco in 1979, and completed her residency in family practice in 1983 at the UC San Francisco affiliated program at Natividad Medical Center of Monterey County, California.
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