Andrea R. Genazzani1, 2 and Nicola Pluchino2
(1)
Obstetrics and Gynecology, University of Pisa, Pisa, Italy
(2)
Obstetrics and Gynecology, University Hospital of Geneva, Geneva, Switzerland
Andrea R. Genazzani
Email: argenazzani@gmail.com
20.1 Introduction
In the last century, longer female life expectancy has implied that women now live a third of their lives beyond the end of their ovarian function, increasing the need for new therapeutic strategies to facilitate successful aging (defined as low probability of disease), high cognitive and physical abilities, and active engagement in life. The incidence of hypertension, diabetes mellitus, psychiatric and degenerative brain diseases, especially stroke and dementia, is more frequently seen in older people. Each of these conditions can, separately or in combination, result in similar signs and symptoms of cognition, memory, mood, and motor functions disorders.
Adrenal and ovarian steroids play pivotal neuroactive and brain region-specific roles. Their protective effects are multifaceted and brain regions dependent. They encompass a system that ranges from chemical to biochemical and genomic mechanisms, protecting against a wide range of neurotoxic insults. Consequently, adrenal and ovarian steroid withdrawal, during the reproductive senescence, impacts negatively the brain function at neuronal, vascular, and metabolic levels.
Convergent evidence for the effects of estrogen on cognitive function comes from studies that have examined cognition in relation to menstrual cycle phase, biomarkers of lifelong estrogen exposure, estrogen receptor polymorphisms, neuroimaging studies, and circulating hormone levels [1–6]. The menopausal transition and aging process represent the main objective of hormone intervention in female life in terms of brain function and cognitive vitality, and several experimental and clinical evidences support this theory. In this chapter, we critically review available evidence on the intriguing hypothesis that the early female brain senescence is a highly responsive period to estrogen treatment for cognitive vitality.
20.2 HRT and Female Cognitive Aging
20.2.1 Longitudinal and Observational Studies
Several observational and longitudinal studies of healthy community-dwelling women suggest that women who use HRT (either unopposed estrogens or estrogens plus progestogen) may perform better on a broad spectrum of cognitive skills or may outperform nonusers on more discrete memory measures. Estrogen users showed significantly higher scores on verbal memory, verbal fluency, and visual memory and higher scores on the Modified Mini-Mental State Examination (3MS) compared with age-matched nonusers [7–10]. In a well-characterized aging cohort in Baltimore, women receiving estrogen performed significantly better than women who had never used estrogen on the Benton Visual Retention Test, a task that measures short-term non-verbal memory and drawing skills [11, 12]. In this study, estrogen users seemed resistant to age-associated declines in the test scores. Because CEE 0.625 mg was the most popular drug and dose used to treat postmenopausal women at the time these studies were undertaken, the vast majority of women who participated were taking CEE 0.625 mg.
The epidemiological data on the neuroprotective effects of estrogen-base therapy were reviewed by Leblanc and colleagues [13]; women who were symptomatic from the menopause had improvement in verbal memory, vigilance, reasoning, and motor speed when given HRT. The same meta-analysis of observational studies examining HRT and cognitive function also suggests a significant reduction in the risk of AD among women who have ever used HRT. In particular, the strongest evidence for an association between HRT and Alzheimer disease comes from two cohort studies: the Manhattan Study of Aging [14] and the Baltimore Longitudinal Study of Aging [12]. The two prospective cohort studies that reported a significantly reduced risk of AD in estrogen users are particularly compelling because they avoid both recall and prescribing practice bias. In the Italian Longitudinal Study on Aging, ERT was associated with a reduced prevalence of AD in 2816 women (OR, 0.24; 95 % CI, 0.07–0.77) [15]. Analysis of observational data from the Cache County Study [16] suggested a reduction in the risk of AD for past HRT users for 3–10 years. In the same study, the “excess” risk of AD when compared with age-equivalent men disappeared among women who received HRT for more than 10 years. However, like the longitudinal studies on estrogen use and cognition, these studies on ERT and the risk for AD show possible biases, which suggest caution in their interpretation. Nevertheless, their findings should be considered consistent in suggesting a protective effect of ERT with regard to the development of AD.
20.2.2 Randomized Controlled Studies
Recent randomized controlled trials (RCTs) of estrogens and cognition have better characterized postmenopausal subjects. Several RCT studies imply that women given estrogen outperformed placebo-treated women on a variety of psychometric measures, including choice reaction time, attention and concentration, distract ability, verbal memory, and abstract reasoning [17]. Sherwin has argued persuasively that estrogen-induced improvement is most apparent on tasks assessing the recall of verbal information, such as recalling details from a paragraph-length narrative [12]. In general, the magnitude of an estrogen effect in healthy women appears to be modest, but in some circumstances, such as surgical menopause, differences appear to be great enough to be clinically meaningful.
A major controversy has been launched during the past 2 years concerning the use of HRT in postmenopausal women [18, 19]. Recent findings from the Women’s Health Initiative Memory Study (WHIMS) indicated an increased risk in long-time postmenopausal women treated with CEE-MPA for diagnosis of probable dementia and mild cognitive impairment compared to placebo. In addition, in the same postmenopausal women aged 65 years or older recruited in the WHIMS, estrogen plus progestin did not improve cognitive function when compared to placebo. Therefore, findings from the estrogen-alone arm of WHIMS indicate that women aged 65 years or older treated with CEE had a slightly lower average cognitive function compared to women assigned to placebo. Moreover, in the same study, the incidence of dementia resulted higher in women receiving CEE-alone compared to the placebo group, but this negative trend did not reach statistical significance [20–23].
The discrepancy between the earlier, smaller RCTs and the WHIMS became apparent, and results from the WHIMS are attributed to the critical issue of the study design; the WHIMS findings do not address the possible role of HRT initiated before the age of 65 years. Group differences in pre-existing risk factors (hypertension, obesity, and diabetes) partly explain the increased rates of adverse vascular effects among women taking HRT [24]. Moreover WHIMS conclusions, like those of the earlier reports of WHI study, are related to the specific strength formulation of hormone therapy and not to different formulations or routes of administration. The oral HT used in WHIMS was either unopposed CEE or continuous combined CEE and medroxyprogesterone acetate. Previous reports suggest that medroxyprogesterone acetate counteracts the beneficial effects of estrogen [25]
The most persuasive explanation for the failure of WHIMS to find a beneficial effect of estrogen on cognition is that the women were too old at the time treatment was initiated for it to have had any protective effect. There are some suggestions that estrogens may be more protective against AD when used by younger postmenopausal women or when initiated at an earlier age.
The analysis of observational data from Cache County Study, suggesting a decreased risk of AD in older HRT user, might be viewed as predicting the WHIMS finding of dementia for women initiating after age 65, with benefit for older women with more typical pattern of past use at a younger age. These issues support the assumption on the presence of a critical period for HRT and related neuroprotection, already raised in the WHIMS accompanying editorial by Schneider [26]. Evidence to support the idea of a window of effectiveness for the initiation of HRT in order to protect against cognitive aging is also raised in the studies of Henderson [27] and Matthews et al. [28]. Similarly, evidence from animal studies indicates that the neuroprotective effects of estrogen and neuroprotection are based on a model of early therapy initiation after the menopause. The importance of timing of initiation of HT and cognitive function is evident in a review of randomized clinical trials of HT and verbal memory [29]. Six of six randomized clinical trials of estrogen therapy in young women demonstrate enhancements in verbal memory. On the contrary, two of two randomized clinical trials of combined oral estrogen and progestogen therapy in older women demonstrate neutral or detrimental effects on verbal memory [30, 31].
Bagger and colleagues demonstrated that women who received HRT in a placebo randomized controlled trials for 2–3 years in the early postmenopausal year have a reduced risk of cognitive impairment 5–15 years later.
In addition, MacLennan et al. present the results of a pilot study (REMEMBER study) examining the timing of initiation of HT on later cognitive function in a population-based study of 428 women. Early initiators of HT performed better than late initiators on the Mini-Mental State Examination and were faster than never-users on the Trail Making Test Part A [32, 33]. The final results from the more representative population-based study will address more consistent data on the “critical window hypothesis” for HRT.
20.3 Evidences and Perspectives in the Post-WHIMS Era
The overall analysis of studies on estrogens and cognitive function from basic science to clinical applications provides some answers for their discrepant findings and suggests new research directions.
Compared to observational and longitudinal studies, randomized controlled trials (RCTs) provide stronger evidence of an estrogen effect on cognition; while the preponderance of findings shows that estrogen users performed better on cognitive tests and experienced less deterioration in aspects of cognition with increasing age than the never-users, findings from longitudinal and observational studies are much more inconsistent that those from the RCTs. Different hypotheses have been argued to explain these differences – the selection bias, since the observational and longitudinal studies encompass self-selected women and usually women taking HRT have better education and higher socio-economical status. Thus, it is difficult to sort out, in these studies, the effects of genetics and environment from the effects of estrogen.
Another point of reflection should be the methodological approach to evaluate cognitive function and brain aging throughout different trials. For the majority of studies, the cognition does not represent the primary endpoint, and many used the 3MSE as the sole measure of cognitive functioning. The 3MSE is an omnibus test of cognitive functioning, which is generally used as a screening instrument to detect cognitive decline, and it is unable to distinguish performance between specific cognitive domains. It is possible that the real effects of estrogen on cognitive protection even with samples of elderly women may have been underestimated due to the lack of precision and specificity of the measuring instrument. Therefore, assessments of specific cognitive functions, such as memory, attention, executive functions (judgment, planning, organization, and cognitive flexibility), language, and spatial ability, are critical for tests of hypotheses regarding effects of estrogens on cognitive function.
Data from the WHI Study of Cognitive Aging (WHISCA), an ancillary study to the WHI and WHIMS, report that the effect of CEE + MPA on cognitive function varies across cognitive domains in older women, reflecting both possible beneficial and detrimental actions of ovarian steroids on the aged brain, suggesting directions for future research [33].
In conclusion, convergent evidences suggest that estrogen treatment has positive effects on aspects of memory and cognition when it is administered to naturally menopausal women shortly after the cessation of their menstrual cycles or immediately following surgical menopause. Data from literature suggest that estrogen treatment to older women have scant beneficial or even detrimental effects on cognitive aging. A “critical period” shortly after menopause, when HT needs to be prescribed to protect cognitive function, has been suggested.
To test the “critical period” hypothesis directly, two recent intervention studies were conducted examining the effects of HT initiation soon after menopause on cognitive function. Firstly, the WHIMS-Young (WHIMS-Y) study investigated 1326 women who had taken part in the WHI CEE-based randomized controlled trials when aged 50–55 years. An average of 14.2 years after randomization to treatment and 7.2 years after treatment discontinuation, when the women were approximately 67.2 years of age, a battery of cognitive tests were administered via a telephone interview [34]. This study addressed the critically important question of whether cognition is impacted years later when women undergo HT during early menopause. Contrary to the initial WHI results, these data indicated neither harm nor benefit to cognitive ability in women initiating HT early in menopause.
An ancillary study of KEEPS, the National Institutes of Health’s National Institute on Aging (NIH-NIA), called the KEEPS Cognitive and Affective study (KEEPS Cog), evaluated the differential efficacy of transdermal estradiol and oral CEE on measures of cognitive function and mood in women enrolled in the parent KEEPS study. The collection of baseline cognitive data from over 700 women enrolled in the KEEPS Cog study was recently completed. The KEEPS Cog study is the first multi-site, randomized, placebo-controlled, double-blind, parallel-group design clinical study that will address major HT-related issues raised by WHI and WHIMS. Specifically, the KEEPS Cog study will compare the differential efficacy of CEE and transdermal estradiol on a comprehensive battery of cognition and mood measures, sensitive to cognition changes associated with HT in perimenopausal and recently postmenopausal women. The hypothesis of the KEEPS Cog study is that, compared to CEE, treatment with transdermal estradiol will enhance cognitive function of healthy peri- and early menopausal women (i.e., decreased rate of cognitive decline or enhanced rate of cognitive improvement compared to placebo-treated group).
Given the adverse findings of WHIMS in postmenopausal women and the fact that HT is still approved for the treatment of menopausal symptoms commonly experienced by younger perimenopausal women, it is critical that the potential cognitive effects of HT, both beneficial and adverse, be identified in women undergoing menopausal transition. The KEEPS Cog study will be the first clinical study to characterize the differential effects of oral CEE and transdermal estradiol on cognitive function of perimenopausal women. As with the WHIMS-Y results, there were neither advantageous nor harmful effects of HT on measures of memory or other cognitive functions. Interestingly, the KEEPS investigators did find an improvement in symptoms of depression and anxiety in women randomized to oral CEE. The major limit of KEEPS Cog is the short follow-up; 4 years might be not sufficient to demonstrate cognitive differences in healthy, well-educated early post-menopausal women [35].
Results of the KEEPS Cog study will provide pivotal data and an exclusive opportunity for future studies to follow the KEEPS cohort over an extended period of 20–25 years to determine whether HT initiated during the perimenopausal period could delay or preferably prevent future development of neurodegenerative diseases like mild cognitive impairment (MCI) and AD.
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