Estradiol treatment and its interaction with the cholinergic system: Effects on cognitive function in healthy young women
Introduction
Over the past three decades the neuroprotective effects of estradiol in the brain and on cognitive functioning has been extensively investigated. A number of comprehensive reviews and meta-analyses of the literature indicate that hormone therapy (HT; either estrogen only treatment [ET] or combined estrogen-progesterone treatment [EPT]) has a small but significant positive effect on measures of verbal memory, abstract reasoning and information processing in post-menopausal women (for reviews see Hogervorst et al., 2000, Sherwin, 2003, Sherwin, 2006, Zec and Trivedi, 2002), although this continues to be debated with several recent studies reporting minimal, negative or no effects (Almeida et al., 2006, Espeland et al., 2004, Lethaby et al., 2008, Resnick et al., 2006, Yaffe et al., 2006). These inconsistencies may be explained by a number of factors, including age, education, general health, socioeconomic status, type, dosage and duration of treatment, length of time between menopause and initiation of treatment, type of menopause (surgical/natural), and climacetric symptoms. Alternatively, the small and inconsistent findings may suggest minimal effects on cognition (for reviews see Lethaby et al., 2008, Sherwin, 2007). Despite the mixed findings from behavioral studies, there has been growing interest in the molecular mechanisms underlying estrogen's neuroprotective effects and it's influence on cognition, particularly given it's potential implications not only for improving cognitive function in patient with Parkinson's Disease and dementia, but also schizophrenia and other mental illnesses (for reviews see Cyr et al., 2002, Garcia-Segura et al., 2001, Halbreich and Kahn, 2003, Osterlund and Hurd, 2001).
Estradiol's interaction with the cholinergic system in particular, has been suggested to partially explain the possible effects on cognitive function (Gibbs, 2000b, Tinkler and Voytko, 2005, Toran-Allerand et al., 1992). This hypothesis is highly feasible given cholinergic input to fronto-limbic and fronto-striatal regions (Selden et al., 1998), and the abundance on evidence supporting this system's prominent role in modulating fundamental cognitive processes, particularly attention, learning, declarative memory and working memory (Ellis et al., 2006, Everitt and Robbins, 1997, Sarter et al., 2005, Hutchison et al., 2001, Thompson et al., 2000). This is further supported by animal studies which show an increase in choline acetyltransferase activity (Gibbs et al., 1994a, Luine, 1985, McMillan et al., 1996) and high-affinity choline uptake (Gibbs, 2000a, Singh et al., 1994) in cortical and subcortical regions following estradiol administration. In addition, estradiol treatment can enhance working memory via interaction with muscarinic (M2) receptors (Daniel et al., 2005) and can protect against the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine, on measures of learning, declarative memory, and working memory in animals (Dohanich et al., 1994, Fader et al., 1998, Fader et al., 1999, Gibbs, 1999, Gibbs et al., 1998, Savonenko and Markowska, 2003, Tanabe et al., 2004).
The interaction between ET and the cholinergic system in humans is less established. Smith et al. (2001) found that length of ET/HT in post-menopausal women was positively correlated with vesicular acetylcholine transporter (VAChT) binding indexes in certain brain regions including the frontal and cingulate cortices, areas essential for attention, learning and memory. However, they were unable to find a difference in VAChT binding between ET/HT users and non-users (Smith et al., 2001). Using Single Photon Emission Tomography (SPET) and a novel muscarinic ligand (R,R) [123I]-I-QNB, Norbury et al. (2007) recently found higher muscarinic receptor density in the striatum, hippocampus, frontal cortex and thalamus of ET/HT users compared to non-users. To date only one research group has investigated the interaction between ET and the cholinergic system with regard to neurocognitive effects. Dumas et al. (2006) found three months of 1 mg/day oral estradiol treatment in post-menopausal women significantly attenuated scopolamine-induced deficits on measures of attention and reaction time. In addition, estradiol treatment also attenuated deficits caused by mecamylamine (a nicotinic receptor antagonist) on two measures of reaction time. However, no interaction between estradiol treatment and the cholinergic system was found on measures on verbal or visual learning and memory, or any of the accuracy/error measures of the attention tasks. More recently Dumas et al. (2008) reported a protective effect of estradiol treatment on episodic memory in younger (aged 50–62) compared to older (aged 70–81) post-menopausal women following a scopolamine challenge, suggesting the possibility of a critical period for ET's beneficial effects on the cholinergic system for women after the menopause.
The possible modulatory effects of estradiol treatment on the cholinergic system in relation to cognition have yet to be investigated in healthy young women of child-bearing age. The current study therefore examined; (a) the effects of one month of 100 μg/day estradiol treatment on cognitive function in a sample of healthy young women and (b) the interaction between estradiol treatment and the cholinergic system, specifically whether one month of estradiol can attenuate the scopolamine-induced deficits in cognitive function for this age group.
Section snippets
Subjects
34 healthy female volunteers (Mean age = 22.59 ± 4.45) aged between 18 and 38 years (Mean weight = 57.87 kg ± 12.57 kg) were recruited for this study from universities around Melbourne. All participants underwent a semi-structured medical screening by a physician who assessed the individual's physical and mental health. Women were excluded if they were pregnant, lactating, peri- or post-menopausal, had a current or past psychiatric illness, had endocrine abnormalities or suffered from any medical
Subjects
Of the 34 participants who enrolled in the study a total of 30 completed both parts One and Two (3 people withdrew due to time constraints and 1 withdrew due to religious commitments). The majority of participants were Australian born, and all spoke fluent English. There were no significant differences in mean age, weight, predicted WAIS-R IQ (as determined by the NART) or nationality found between the two groups (see Table 1). Independent samples t-tests conducted on each cognitive measure at
Discussion
The current study examined the cognitive effects of one month estradiol treatment and its interaction with the cholinergic system in healthy young women of child-bearing age. The findings showed that estradiol treatment; (1) enhanced accuracy on a measure of working memory, had a tendency to improve long-term verbal memory but had no effect on verbal fluency, cognitive flexibility, attention or information processing and psychomotor functioning, and (2) overall, did not protect against the
Acknowledgments
The authors wish to thank the Australian Rotary Health Research Fund for fellowship support for Cali Bartholomeusz and the National Health and Medical Research Council (NHMRC) for fellowship support for Pradeep Nathan. We would also like to thank Susan Illic for performing medical examinations and all the nurses from the School of Integrative Medicine, Swinburne University who administered the scopolamine and placebo injections, in particular Susan Vitetta who kindly gave up her free time to
References (106)
- et al.
Association between physiological serum concentration of estrogen and the mental health of community-dwelling postmenopausal women age 70 years and over
Am. J. Geriatr. Psychiatry
(2005) - et al.
A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life
Neurobiol. Aging
(2006) - et al.
Role of hippocampal M2 muscarinic receptors in the estrogen-induced enhancement of working memory
Neuroscience
(2005) - et al.
Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis
Horm. Behav.
(2008) - et al.
Estrogen and progesterone treatment: effects on muscarinic M(4) receptor subtype in the rat brain
Brain Res.
(2002) - et al.
Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally
Neurobiol. Learn. Mem.
(1998) - et al.
Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze
Pharmacol. Biochem. Behav.
(1999) - et al.
Interaction of age and chronic estradiol replacement on memory and markers of brain aging
Neurobiol. Aging
(2003) Estrus-associated decrements in a water maze task are limited to acquisition
Physiol. Behav.
(1995)- et al.
Sex differences in the activational effect of ERalpha on spatial learning
Horm. Behav.
(1998)
Gonadal hormone levels and spatial learning performance in the Morris water maze in male and female meadow voles, Microtus pennsylvanicus
Horm. Behav.
Neuroprotection by estradiol
Prog. Neurobiol.
Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function
Exp. Neurol.
Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition
Horm. Behav.
Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function
Neuroscience
Effects of estrogen replacement on the relative levels of choline acetyltransferase, trkA, and nerve growth factor messenger RNAs in the basal forebrain and hippocampal formation of adult rats
Exp. Neurol.
Effects of estrogen replacement on the relative levels of choline acetyltransferase, trkA, and nerve growth factor messenger RNAs in the basal forebrain and hippocampal formation of adult rats
Exp. Neurol.
Estrogen replacement attenuates effects of scopolamine and lorazepam on memory acquisition and retention
Horm. Behav.
Endocrine disruption and cognitive function in adolescent female rhesus monkeys
Neurotoxicol. Teratol.
No difference in cognitive performance between phases of the menstrual cycle
Psychoneuroendocrinology
Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans
Pharmacol. Biochem. Behav.
Hormonal aspects of schizophrenias: an overview
Psychoneuroendocrinology
Estrogen-related variations in human spatial and articulatory-motor skills
Psychoneuroendocrinology
Variations in sex-related cognitive abilities across the menstrual cycle
Brain Cogn.
The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis
Neuroscience
Psychological aspects of premenstrual syndrome. I: Cognition and memory
Psychoneuroendocrinology
A 3-day estrogen treatment improves prefrontal cortex-dependent cognitive function in postmenopausal women
Psychoneuroendocrinology
Estrogen — a potential treatment for schizophrenia
Schizophr. Res.
Hormone replacement therapy and cognition in an Australian representative sample aged 60–64 years
Maturitas
Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats
Exp. Neurol.
Implicit memory varies across the menstrual cycle: estrogen effects in young women
Neuropsychologia
Estrogen therapy and brain muscarinic receptor density in healthy females: a SPET study
Horm. Behav.
Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders
Prog. Neurobiol.
Variations in memory function and sex steroid hormones across the menstrual cycle
Psychoneuroendocrinology
Verbal and spatial functions across the menstrual cycle in healthy young women
Psychoneuroendocrinology
Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection
Brain Res. Brain Res. Rev.
The cognitive effects of ovariectomy and estrogen replacement are modulated by aging
Neuroscience
Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study
Psychoneuroendocrinology
Estrogen and cognitive aging in women
Neuroscience
Sources of estrogen and their importance
J. Steroid Biochem. Mol. Biol.
Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague–Dawley rats
Brain Res.
Estrogen modulates cognitive and cholinergic processes in surgically menopausal monkeys
Prog. Neuropsychopharmacol. Biol. Psychiatry
Performance and state changes during the menstrual cycle, conceptualised within a broad band testing framework
Soc. Sci. Med.
Estrogen effects on object memory and cholinergic receptors in young and old female mice
Neurobiol. Aging
Estrogen therapy and cognition: a 6-year single-blind follow-up study in postmenopausal women
Neurology
Cycle control with triphasic norgestimate and ethinyl estradiol, a new oral contraceptive agent
Acta. Obstet. Gynecol. Scand.
High-dose estradiol improves cognition for women with AD: results of a randomized study
Neurology
Multilingual Aphasia Examination
The use of analogue scales in rating subjective feelings
Br. J. Med. Psychol.
Effects of estrogen on muscarinic acetylcholine receptors in the rat hippocampus
Neuroendocrinology
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Attentional networks during the menstrual cycle
2022, Behavioural Brain ResearchCitation Excerpt :The accumulative literature shows inconsistent results, making it more difficult to predict a one-directional hypothesis. Moreover, E2 and P4 influence various neurochemical systems implicated in attention [15,16,31,4,9]. Some of these systems (e.g., dopamine or GABA) function with an inverted-U, rather than a linear, shape of action.
Estradiol effects on spatial memory in women
2022, Behavioural Brain ResearchCitation Excerpt :Another study found that with administration of estradiol via a transdermal skin patch for 31 days, performance on a spatial working memory version of an N-back task and verbal recollection were enhanced in the estradiol-treated group compared to the non-treated group [4]. However, there was no effect of the estradiol treatment on verbal fluency, attention on the Stroop task, or information processing [4]. These data suggest that natural reductions in estrogens during the menstrual cycle may result in cognitive impairments.
Structure-function-behavior relationship in estrogen-induced synaptic plasticity
2015, Hormones and BehaviorCitation Excerpt :Interestingly, another MRI study that reported larger hippocampal volumes in women who initiated hormone treatment at menopause did not observe differences in spatial memory performance (Erickson et al., 2010). The pharmacological administration of estradiol in younger women led to a slight improvement in verbal memory in some studies (Bartholomeusz et al., 2008; Phillips and Sherwin, 1992a; Sherwin, 1998; Sherwin and Tulandi, 1996). Natural fluctuations in estradiol across the menstrual cycle are associated with fluctuations in verbal, emotional and spatial memory performance in some studies (Ertman et al., 2011; Solis-Ortiz and Corsi-Cabrera, 2008) and, in particular, menstrual cycle-dependent changes in verbal memory occurred simultaneously to changes in hippocampal volume (Protopopescu et al., 2008).
Estradiol concentrations and working memory performance in women of reproductive age
2013, PsychoneuroendocrinologyCitation Excerpt :Practice effects were not controlled and neither the improvement on Day 7 nor the relatively poor performance on Day 21 suggests an estradiol effect. Bartholomeusz et al. (2008) found inconsistent effects of a 100 μg/day estradiol treatment on an n-back task, with improvement in the 1- but not 2-back condition, but failed to suppress the menstrual cycle, complicating interpretation. Estradiol was not measured in any of these studies, obscuring the potential to detect significant correlations between estradiol levels and WM performance.