Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women - The Women's Health Initiative Memory Study: A Randomized Controlled Trial

Harvard University, Cambridge, Massachusetts, United States
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 05/2003; 289(20):2663-72. DOI: 10.1001/jama.289.20.2663
Source: PubMed


Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women.
To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women.
A randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002.
Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236).
Global cognitive function measured annually with the Modified Mini-Mental State Examination.
The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (> or =2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P =.008).
Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.

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Available from: Karen C Johnson
    • "Until relatively recently, estrogen replacement with and without progesterone was a popular hormone therapy to protect against the symptoms of hormone loss, including changes in cognitive function, as women transition through menopause. However the health benefits of estrogens were challenged by the findings from the Women's Health Initiative (WHI) reports, and the subsequent fallout from and the media surrounding the reports, suggesting that conjugated equine estrogens and synthetic progestins found in the commonly prescribed hormone replacement treatment Premarin® and Prempro® can increase risk for various cancers, stroke, and potentially Alzheimer's disease (Espeland et al., 2004; Rapp et al., 2003; Rossouw et al., 2002; Shumaker et al., 2003). These findings were used to support the view that ovarian steroids may be detrimental to health and to brain health in particular. "
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    ABSTRACT: Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Hormones and Behavior
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    • "Accumulating evidences support that E2 pretreatment can induce neuroprotection in brain injuries 2. However, clinical trials have generated controversial reports regarding the effect of estrogen replacement therapy on stroke in postmenopausal women 26, 27. Also, since estrogen replacement therapy is also associated with some undesirable adverse effects, it may not be a suitable alternative in this population 28, 29. "
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    ABSTRACT: Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.
    Preview · Article · Apr 2014 · International journal of biological sciences
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    • ") not only failed to positively affect conditions associated with neuroprotection , but that ET or combined hormone therapy ( HT ) may worsen cognition ( Espeland et al . , 2004 ; Rapp et al . , 2003 ; Shumaker et al . , 2003 , 2004 ; Mul - nard et al . , 2000 ) and increase strokes ( Rossouw et al . , 2002 ; Man - son et al . , 2003 ; Anderson et al . , 2004 ) and cardiac arrests ( Rossouw et al . , 2002 ; Manson et al . , 2003 ) . Reanalysis of the WHI data , however , indicates that early post - menopausal treat - ment with estro"
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    ABSTRACT: Studies have shown differences in specific cognitive ability domains and risk of Alzheimer's disease between the men and women at later age. However it is important to know that sex differences in cognitive function during adulthood may have their basis in both organizational effects, i.e., occurring as early as during the neuronal development period, as well as in activational effects, where the influence of the sex steroids influence brain function in adulthood. Further, the rate of cognitive decline with aging is also different between the sexes. Understanding the biology of sex differences in cognitive function will not only provide insight into Alzheimer's disease prevention, but also is integral to the development of personalized, gender-specific medicine. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of sex differences in cognitive function from young to old, and examines the effects of sex hormone treatments on Alzheimer's disease in men and women.
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