Estrogen Therapy and brain muscarinic receptor density in healthy females: A SPET study

Psychopharmacology and Emotion Research Laboratory, University of Oxford, UK.
Hormones and Behavior (Impact Factor: 4.63). 03/2007; 51(2):249-57. DOI: 10.1016/j.yhbeh.2006.10.007
Source: PubMed


Estrogen Therapy (ET) may protect against age-related cognitive decline and neuropsychiatric disorders (e.g. Alzheimer's disease). The biological basis for this putative neuroprotective effect is not fully understood, but may include modulation of cholinergic systems. Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer's disease. However, to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging, and related this to cognitive function. We used Single Photon Emission Tomography (SPET) and (R,R)[(123)I]-I-QNB, a novel ligand with high affinity for m(1)/m(4) muscarinic receptors, to examine the effect of long-term ET and age on brain m(1)/m(4) receptors in healthy females. We included 10 younger premenopausal subjects and 22 postmenopausal women; 11 long-term ET users (all treated following surgical menopause) and 11 ET never-users (surgical menopause, n=2). Also, verbal memory and executive function was assessed in all postmenopausal subjects. Compared to young women, postmenopausal women (ET users and never-users combined) had significantly lower muscarinic receptor density in all brain regions examined. ET users also had higher muscarinic receptor density than ET never-users in all the brain regions, and this reached statistical significance in left striatum and hippocampus, lateral frontal cortex and thalamus. Moreover, in ET users, (R,R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels. We also found evidence for improved executive function in ET users as compared to ET never-users. However, there was no significant relationship between receptor binding and cognitive function within any of the groups. In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding, and this may be related to serum estradiol levels.

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    • "In human females, variations in estradiol during the natural menstrual cycle are also associated with mood changes (Derntl et al., 2008; McEwen, 2010): a negative affect is more commonly experienced when estrogen levels are declining or low; whereas a positive affect is associated with high estrogen levels, according to the significant modulatory effects of estrogen upon neurotransmitter systems involved in the regulation of affective behavior (Amin et al., 2006a,b; Norbury et al., 2007). Women with mood disorders show definite peaks that are temporally related to periods of substantial hormonal fluctuation (e.g., adolescence, the week before the onset of menses and perimenopause; Sigmon et al., 2000). "
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    ABSTRACT: Abstract Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions, including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines, serotonin and GABA in rodents, primates and humans. Another reason may lie in the widespread presence of the two classes (α and β) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section, focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle.
    Reviews in the neurosciences 08/2012; 23(5-6). DOI:10.1515/revneuro-2012-0051 · 3.33 Impact Factor
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    • "The consistent findings from the observational studies reviewed above seem to be that ERT (most commonly CEE), with a minimal duration of at least one year, is beneficial in reducing risk for AD among healthy postmenopausal women. Although benefits have been observed among varied regimens (CEE, CEE + P, E2) [48, 51, 52]; the most beneficial estrogen formulation seems to be E2 unopposed by progestin [24, 50]. Randomized clinical trials in healthy, postmenopausal women have suggested that E2 has been most beneficial in reducing cognitive decline, particularly verbal memory, which is the predominant symptom of early AD [18, 22–24]. "
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    ABSTRACT: Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT) with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer's disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson's disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson's-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.
    International Journal of Alzheimer's Disease 04/2012; 2012(2):258454. DOI:10.1155/2012/258454
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    • "Growing evidence suggests that estrogen affects cognition through its neuromodular effect on the cholinergic (Norbury et al., 2007), the serotoninergic (Bethea, Lu, Gundlah, & Streicher, 2002), and the GABA system (Amin et al., 2006). However, the dopaminergic system seems to be particularly strongly affected by estrogen. "
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    ABSTRACT: Estrogen has a key role in explaining gender differences in dopaminergic functioning. To date, previous studies on estrogen have focused on inhibitory output control, such as the intentional suppression of overt pre-potent actions, but whether input control is also modulated is an open question. For the first time, this study compared the ability to perform a cued target-detection task that measured inhibition of return (IOR), a reflexive inhibitory mechanism that delays attention from returning to a previously attended location, in young women (n=21) across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men (n=21). Women showed more pronounced IOR effect in their follicular phase, which is associated with both higher estradiol levels and higher dopamine turnover rates, than in their luteal or menstruation phase. This increase in women's IOR in their follicular phase was also greater than the effect found for men at any of the three phases. Our results are consistent with the idea that estrogen promotes IOR. Given that the mechanism underlying IOR biases the cognitive system towards the intake of novel information, our findings suggest that when the estrogen level is high, women are biased towards cognitive flexibility rather than cognitive stability. We conclude that gender differences in inhibitory input control are variable and state-dependent but not structural.
    Neuropsychologia 11/2011; 50(1):98-103. DOI:10.1016/j.neuropsychologia.2011.11.003 · 3.30 Impact Factor
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