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Effects of treatment with leuprolide acetate depot on working memory and executive functions in young premenopausal women

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Abstract

The goal of this study was to assess the influence of sex steroid hormone suppression on performance on tests of prefrontal cortex (PFC) and working memory function (WM) in premenopausal women. Twenty-five women were treated with leuprolide acetate depot (LAD), a gonadotropin releasing hormone (GnRH) analog that chemically suppressed ovarian function as treatment of various benign gynecologic disorders. Performance on tests of PFC and WM of the LAD-treated women was assessed at pretreatment baseline and, again, following 4 weeks of treatment and their performance was compared to that of 25 healthy, control participants matched on age, education, and general intelligence. Following 4 weeks of LAD treatment, estrogen levels decreased to the postmenopausal range whereas progesterone levels fell to the lower limit of the menstrual cycle range of values. Furthermore, the LAD-treated women also experienced a significant deterioration in mood, in health-related symptoms and in performance on two tests of WM following 4 weeks of treatment. It was determined that only the post-treatment declines in estrogen, but not those in progesterone, in mood, or in health-related symptoms were associated with the worsening of performance on the WM tests. These findings provide new evidence that estrogen is influential in the maintenance of WM processes in premenopausal women.

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... Participants were given both 1-back and 2-back subtasks, allowing the examination of load effects. A 3-back subtask was not included as it was deemed to be too taxing for most older participants (Grigorova, Sherwin, & Tulandi, 2006). ...
... This may provide an argument for further efforts to increase the educational level of women, in particular in non-Western societies such as Taiwan, where the educational level of females has only started to approach that of males in the past 50 years (Thornton et al., 1984;Tsai et al., 1994). It is also possible that pharmacological analogues of sex hormones, or perhaps other pharmacological agents that improve memory, could be employed in older adults to ameliorate WM (Grigorova et al., 2006;Keenan et al., 2001;Ullman & Pullman, 2015). ...
... First of all, females may show a particular decrease in WM abilities during menopause, likely due to estrogen loss(Almela, van der Meij, Hidalgo, Villada, & Salvador, 2012;Weber & Mapstone, 2009;Weber, Mapstone, Staskiewicz, & Maki, 2012). Indeed, research has shown a positive association between estrogen and WM Working memory in older adults 33 performance(Grigorova et al., 2006;Keenan, Ezzat, Ginsburg, & Moore, 2001). A menopause-related decline in WM in females is also consistent with the suggestion from the broader literature that male advantages in WM are less reliably observed in younger adults, in particular for verbal WM (see Introduction). ...
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Working memory (WM), which underlies the temporary storage and manipulation of information, is critical for multiple aspects of cognition and everyday life. Nevertheless, research examining WM specifically in older adults remains limited, despite the global rapid increase in human life expectancy. We examined WM in a large sample (N = 754) of healthy older adults (aged 58-89) in a non-Western population (Chinese speakers) in Taiwan, on a digit n-back task. We tested not only the influence of age itself and of load (1-back vs. 2-back) but also the effects of both sex and education, which have been shown to modulate WM abilities. Mixed-effects regression revealed that, within older adulthood, age negatively impacted WM abilities (with linear, not nonlinear, effects), as did load (worse performance at 2-back). In contrast, education level was positively associated with WM. Moreover, both age and education interacted with sex. With increasing age, males showed a steeper WM decline than females; with increasing education, females showed greater WM gains than males. Together with other findings, the evidence suggests that age, sex, and education all impact WM in older adults, but interact in particular ways. The results have both basic research and translational implications and are consistent with particular benefits from increased education for women.
... Second, performance on several cognitive measures varies across the menstrual cycle (e.g., motor dexterity, verbal fluency, visuospatial ability, implicit memory) (Hampson and Kimura, 1988;Maki et al., 2002) and correlates with levels of circulating sex steroids. Third, cognitive changes are observed after manipulations of sex steroids in both women and men (Sherwin and Tulandi, 1996;Grigorova et al., 2006;Cherrier et al., 2008). Fourth, albeit controversial, sex steroids have putative benefits in the treatment of cognitive dysfunction (acute and prophylactic effects) in some studies (LeBlanc et al., 2001;Yaffe et al., 1998;Cherrier et al., 2001;Wolf et al., 1999;Maki et al., 2001;Joffe et al., 2006;Smith et al., 2001;Cherrier, 2009;Cherrier et al., 2005). ...
... In contrast, with the exception of paragraph memory [immediate] scores, no significant sex differences were observed in the performances on the other cognitive domains measured (i.e., attention, concentration, and motor speed and dexterity). Finally, in contrast to some reports in the literature (Cherrier et al., 2003;Grigorova et al., 2006), our findings also show that induced hypogonadism has few detrimental (Hier and Crowley, 1982) effects on visuospatial performance in either women or men, suggesting that, at least in the short term, the relative absence of circulating sex steroids does not impair visuospatial task performance in women or men. ...
... Previous studies demonstrate the beneficial effects of estrogen therapy in older hypogonadal (post-menopausal) women on measures of verbal and visual memory in some (Kampen and Sherwin, 1994;Resnick et al., 1997;Joffe et al., 2006;Maki et al., 2001) but not all studies (Berman et al., 1997;Shaywitz et al., 1999;LeBlanc et al., 2001;Keenan et al., 2001). Additionally, several reports examined the effects of hypogonadism on cognitive performance in younger women receiving GnRH agonists for uterine fibroids or endometriosis (Sherwin and Tulandi, 1996;Grigorova et al., 2006), and in contrast to our data, the majority of these studies (Palomba et al., 2004;Craig et al., 2008a;Craig et al., 2008b;Craig et al., 2007;Varney et al., 1993) observed a significant decline in performance scores in measures of verbal memory, working memory, and visual recognition during hypogonadism compared with baseline. We were unable to identify significant declines in performance scores in tests of attention or verbal or visual memory during hypogonadism in this study. ...
Article
Background: Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates. Objective: To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism. Methods: Men (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models. Results: During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects). Conclusion: The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus sex differences in visuospatial performance in adulthood could reflect early developmental effects of sex steroid exposure or other environmental exposures differing across the sexes as our data confirm that these differences are independent of circulating estradiol or testosterone levels in men and women.
... Improved performance on measures of verbal and spatial working memory has been observed in several studies of postmenopausal women receiving estrogen treatment (Duff & Hampson, 2000;Krug, Born, & Rasch, 2006; but see Grigorova & Sherwin, 2007) and in young women with healthy menstrual cycles in whom circulating estradiol levels were negatively correlated with errors on a spatial working memory task (Hampson & Morley, 2013). Conversely, women treated with a drug that inhibited gonadotropin production, causing ovarian function to be suppressed, showed poorer performance on the n-back task compared to pre-treatment and compared with matched controls (Grigorova, Sherwin, & Tulandi, 2006). ...
... Limitations of the present study include the fact that we could not control phase of the menstrual cycle when testing our female group. Given the increasing evidence that circulating estrogens play a role in the functioning of the working memory system (e.g., Duff & Hampson, 2000;Grigorova et al., 2006;Hampson & Morley, 2013;Krug et al., 2006), allowing the menstrual cycle to vary randomly may have resulted in uncontrolled variability in the female data that attenuated the size of any sex difference. Sex differences on tasks that are estrogen-sensitive may be susceptible to the variability in steroid levels over the course of the menstrual cycle, whereas sex differences on androgen-sensitive tasks may be more robust due to the large difference between males and females in androgen levels and/or an organizational origin. ...
Article
There is preliminary evidence to suggest that the prefrontal cortex (PFC) is modulated by sex steroids in humans and other primates. The current study examined whether sex differences in performance could be discerned on two working memory tasks that emphasize monitoring and updating processes, and on two tasks that engage the ventromedial PFC/orbitofrontal cortex (VMPFC/OFC). Healthy young adults (48 females; 45 males) completed the n-back, Self-Ordered Pointing (SOP), Iowa Gambling Task (IGT), and a probabilistic reversal learning task. On the IGT, males selected more cards from the advantageous decks than females. On the reversal learning task, there was no significant sex difference in acquisition of the reinforcement contingencies, but males made fewer errors than females during the reversal phase. The sexes did not differ significantly on the n-back or SOP tasks. These findings provide tentative support for the hypothesis that functions carried out by the VMPFC/OFC are sexually differentiated in humans. Copyright © 2014 Elsevier Inc. All rights reserved.
... Clinic-based observational studies (7,8) and some treatment studies (11,12) have implicated changes in hormonal events during the menopause transitionin particular, estradiol withdrawal-in the onset of depression. Finally, in at least five studies, which together include over 70 premenopausal women, a greater-thanexpected frequency of clinically significant mood symptoms was observed when a gonadotropin-releasing hormone (GnRH) agonist was used to suppress ovarian function (13)(14)(15)(16)(17)(18). ...
... These findings are consistent with those of both Bloch et al. (27) and Owens et al. (28), who reported the absence of significant mood changes after GnRH agonist treatment. Against these findings, several other clinic-based studies reported that GnRH agonist-induced ovarian suppression was associated with depression that was sufficiently severe in some women to warrant antidepressant medication (13)(14)(15)(16)(17)29). Depressive symptoms associated with GnRH agonist ovarian suppression could reflect the effects of ovarian suppression in women who are more vulnerable to the development of depression or who are currently depressed. ...
Article
Objective: The relationship between depression and estrogen withdrawal remains controversial. The authors examined the effects of gonadotropin-releasing hormone agonist-induced ovarian suppression on mood, sleep, sexual function, and nighttime hot flushes. They focused on whether participating women experienced clinically significant depressive symptoms and whether specific symptoms associated with hypogonadism (nighttime hot flushes and disturbed sleep) increased susceptibility to depression. Method: Participants were 72 healthy premenopausal women, ages 19-52 years, with no current or past axis I psychiatric diagnosis or gynecological or other medical illness. After 2 months of baseline screening, women received monthly injections of leuprolide acetate (3.75 mg) for 2-3 months. Outcomes were measured using the Beck depression inventory (BDI) and a daily rating scale measuring the severity of several affective and behavioral symptoms. Data were analyzed by repeated-measures analysis of variance using PROC MIXED (for mixed models). Results: BDI scores ≥10 were reported in four of the 72 women (5.6%). Relative to baseline, induced hypogonadism was associated with significantly decreased sexual interest, disturbed sleep, and more severe nighttime hot flushes, but no significant change in any mood-related symptom score. Hot flush severity was significantly correlated with disturbed sleep. Conclusions: These data demonstrate that clinically significant depressive symptoms were rare accompaniments of short-term estradiol withdrawal and induced hypogonadism in healthy premenopausal women. Additionally, neither nighttime hot flushes nor disturbed sleep were sufficient to cause depressive symptoms in hypogonadal women.
... In parallel, nonhuman primate studies have made substantial progress toward characterizing the role of estradiol in PFC synaptic plasticity and PFC-mediated cognitive functions (Hao et al., 2006;Morrison et al., 2006;Wang et al., 2010;Rapp et al., 2003). Mounting evidence from human neuroimaging studies further implicates sex steroids in the regulation of memory circuitry (Berman et al., 1997;Shaywitz et al., 1999;Duff and Hampson, 2000;Sherwin, 2003;Grigorova et al., 2006;Dumas et al., 2010;Jacobs and D'Esposito, 2011;Epperson et al., 2012;Hampson and Morley, 2013;Shanmugan and Epperson, 2014;Jacobs et al., 2016). This research builds on the pioneering work of Berman et al. (1997) and Shaywitz et al. (1999), who used pharmacological blockade and hormone replacement techniques to illustrate estradiol and progesterone's influence on regional activity in memory circuitry. ...
... Together, these findings provide converging evidence that functional changes in estrogen receptor-rich regions of memory circuitry are tied to ovarian status. Thus, the decline in ovarian estradiol production during the menopausal transition in women may impact specific neural circuits early in the aging process (Hogervorst et al., 2000;Adams et al., 2002;Morrison et al., 2006;Sherwin, 2006;Brinton 2009;Boulware et al., 2012;Maki and Henderson, 2012;Epperson, 2013;Jacobs et al., 2016). In this population-based functional MRI study of early midlife men and women (N ϭ 200; age range, 45-55), we demonstrate that regional and network-level changes in memory circuitry during verbal encoding are evident early in the aging process as a function sex, women's reproductive stage, and sex steroid hormone concentrations. ...
Article
Unlabelled: Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry. Significance statement: Maintaining intact memory function with age is one of the greatest public health challenges of our time, and women have an increased risk for memory disorders relative to men later in life. We studied adults early in the aging process, as women transition into menopause, to identify neuronal and cognitive changes that unfold in the middle decades of life. Results demonstrate regional and network-level differences in memory encoding-related activity as a function of women's reproductive stage, independent of chronological age. Analyzing data without regard to sex or menopausal status obscured group differences in circuit-level neural strategies associated with successful memory retrieval. These findings suggest that early changes in memory circuitry are evident decades before the age range traditionally targeted by cognitive neuroscience of aging studies.
... Given that the pubertal transition is driven by changes in secretion of the hormone gonadotropin releasing hormone (GnRH), to identify hormonal mechanisms that might underlie sex differences in brain development and cognitive function, several studies have investigated the modulatory effect of GnRH (Bryan et al., 2010;Grigorova et al., 2006;Wojniusz et al., 2011) and it's agonist (GnRHa) on psychomotoric reactivity, cognitive parameters and gene expression in the hippocampus (Evans et al., 2012;Nuruddin et al., 2013;Wojniusz et al., 2011). GnRH is synthesized in specialized neurons in the brain and released into the hypophysial portal blood vessels to act on receptors in the anterior pituitary gland (Millar, 2005). ...
... These brain areas are rather involved in cognitive functions, for example; memory, emotions and learning (Albertson et al., 2008;Chu et al., 2010;Schang et al., 2011;Skinner et al., 2009;Wilson et al., 2006). Interestingly, long term GnRHa treatment has been reported to lead to impairment of higher-order executive control functions, the processing of visuo-spatial information (Nelson et al., 2008) and working memory (Bryan et al., 2010;Grigorova et al., 2006) in adult humans that suggests a physiological role for GnRH in these brain areas. Similarly, in animal models of Alzheimer's disease (AD), improvements in cognitive function have been reported due to GnRHa treatment (Bowen et al., 2004;Casadesus et al., 2006) and these studies, in combination with others, have led to clinical interest in GnRHa therapy for this condition (Doraiswamy and Xiong, 2006). ...
Article
The nature of hormonal involvement in pubertal brain development has attracted wide interest. Structural changes within the brain that occur during pubertal development appear mainly in regions closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors, results in exaggerated sex-differences in cognitive executive function and emotional control, as well as sex and hemisphere specific patterns of expression of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explored effects of this treatment regime on the gene expression profile of the ovine amygdala.
... Estrogens in particular could be relevant. Behavioral (Duff and Hampson, 2000;Grigorova et al., 2006;Hampson and Moffat, 2004;Hampson and Morley, 2013;Krug et al., 2006), functional imaging (Joffe et al., 2006;Smith et al., 2006), and nonhuman primate studies (Rapp et al., 2003) increasingly suggest that in other contexts estrogens do influence the PFCdependent WM system, but pregnancy has not been studied. Investigations of WM in postmenopausal women (e.g., Duff and Hampson, 2000;Keenan et al., 2001;Krug et al., 2006) or over the natural menstrual cycle (Hampson and Morley, 2013) would predict a positive effect of high estrogens on WM during gestation, not a negative one as implied by reports of GMI. ...
... This may also be true during pregnancy (when not impaired by an overlay of depression). The present study is the first to discover an association between estradiol and WM during pregnancy, but previous work has revealed that WM is better in postmenopausal women or nonhuman primates treated with estrogens compared with untreated controls (Duff and Hampson, 2000;Keenan et al., 2001;Krug et al., 2006;Rapp et al., 2003), and improves at high estradiol phases of the menstrual cycle compared with low (Hampson and Moffat, 2004;Hampson and Morley, 2013), while WM is diminished by leuprolide acetate, a medication which suppresses ovarian function (Grigorova et al., 2006). Functional imaging studies using randomized placebo-controlled designs show that estradiol administration alters regional activation levels seen in the PFC during the performance of WM tasks (Smith et al., 2006). ...
Article
Full-text available
Subjective changes in concentration and memory are commonly reported by women during the second or third trimesters of pregnancy, but the nature of the problem is poorly understood. We hypothesized that these self-reports might reflect difficulties in working memory (WM). It was further hypothesized that antepartum depression (depression arising during pregnancy) may play an etiological role, either on its own or due to secondary changes in endocrine function or sleep. Using WM tasks that emphasized executive control processes mediated by the prefrontal cortex (PFC) we compared pregnant women tested at 34-36 weeks gestation (n=28) with age- and education-matched non-pregnant controls (n=26). All pregnant women were screened for depression. Evidence of a WM disturbance was found, and was evident only among pregnant women showing depressive symptoms. In contrast, pregnant women who were not depressed showed WM performance that equalled, or even significantly exceeded, non-pregnant controls. No significant differences were observed on control tests of other cognitive functions. Multiple regression revealed that serum estradiol concentrations, along with severity of depressive affect but not sleep disruption, significantly predicted variation in the WM scores. In agreement with studies of estradiol and WM in other contexts, higher estradiol was associated with better WM, while higher levels of depressive symptoms predicted poorer WM. We conclude that memory disturbance during gestation might not be as widespread as commonly believed, but can be seen among women experiencing antepartum depression. The high level of WM performance found in healthy, non-depressed, pregnant women is discussed from an adaptationist perspective. Copyright © 2015. Published by Elsevier Inc.
... Performance on tasks requiring attention and planning was shown to depend on estrogen and progesterone levels in premenopausal women [Solis-Ortiz et al., 2004]. In contrast, another study assessing the effects of hormone suppression in premenopausal women found that an induced decline in estrogen, but not progesterone, was sufficient to induce working memory impairments [Grigorova et al., 2006]. PET imaging studies demonstrate significant increases in 5-HT 2A receptor binding in multiple brain regions in postmenopausal women receiving ET [Kugaya et al., 2003], although there is some evidence that progesterone in addition to estrogen is needed to significantly increase 5-HT 2A binding in the DLPFC [Moses et al., 2000]. ...
Article
Midlife decline in cognition, specifically in areas of executive functioning, is a frequent concern for which menopausal women seek clinical intervention. The dependence of executive processes on prefrontal cortex function suggests estrogen effects on this brain region may be key in identifying the sources of this decline. Recent evidence from rodent, nonhuman primate, and human subject studies indicates the importance of considering interactions of estrogen with neurotransmitter systems, stress, genotype, and individual life events when determining the cognitive effects of menopause and estrogen therapy. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
... Also, men tend to show bilateral activation or right-sided dominance during the completion of this task, whereas women predominantly show left-sided activation (12). There are indications that menstrual cycle pattern-dependent E 2 levels relate to working memory (13,14). It is, however, unclear whether changes in androgen levels affect working memory processes as well (15)(16)(17). ...
... Notably, the sexual dimorphism in mPFC-dependent processes is attenuated by hormonal fluctuations throughout a woman's reproductive life or within the menstrual cycle [9,10]. Indeed, a growing body of evidence suggests that fluctuations in circulating levels of estrogens in postmenopausal women or healthy cycling women can affect PFC-dependent working memory and executive functions [4,[11][12][13][14]. Surprisingly, despite the vast genomic effects of ovarian hormones in the rodent mPFC [15], the effect of the estrous cycle on the mPFC transcriptome and subsequent interaction with cognitive functions and emotional processing remain to be investigated. ...
Article
Full-text available
Background: Males and females differ in cognitive functions and emotional processing, which in part have been associated with baseline sex differences in gene expression in the medial prefrontal cortex. Nevertheless, a growing body of evidence suggests that sex differences in medial prefrontal cortex-dependent cognitive functions are attenuated by hormonal fluctuations within the menstrual cycle. Despite known genomic effects of ovarian hormones, the interaction of the estrous cycle with sex differences in gene expression in the medial prefrontal cortex remains unclear and warrants further investigations. Results: We undertake a large-scale characterization of sex differences and their interaction with the estrous cycle in the adult medial prefrontal cortex transcriptome and report that females with high and low ovarian hormone levels exhibited a partly opposed sexually biased transcriptome. The extent of regulation within females vastly exceeds sex differences, and supports a multi-level reorganization of synaptic function across the estrous cycle. Genome-wide analysis of the transcription factor early growth response 1 binding highlights its role in controlling the synapse-related genes varying within females. Conclusions: We uncover a critical influence of the estrous cycle on the adult rat medial prefrontal cortex transcriptome resulting in partly opposite sex differences in proestrus when compared to diestrus females, and we discovered a direct role for Early Growth Response 1 in this opposite regulation. In addition to illustrating the importance of accounting for the estrous cycle in females, our data set the ground for a better understanding of the female specificities in cognition and emotional processing.
... It is likely that these effects are not a direct consequence of the GnRHa but rather an indirect effect of reduced estradiol and progesterone levels in the brain. However, though the pseudo menopause produced by GnRHa is a powerful model, the impact of short-term ovarian suppression on cognition in young premenopausal women seems to be contradictory; in some cases strong (Sherwin and Tulandi, 1996;Grigorova et al., 2006), and in other cases only marginal (Rocca et al., 2014) or absent (Owens et al., 2002). ...
Article
Full-text available
The level of gonadal hormones to which the female brain is exposed considerably changes across the menopausal transition, which in turn, is likely to be of great relevance for neurodegenerative diseases and psychiatric disorders. However, the neurobiological consequences of these hormone fluctuations and of hormone replacement therapy in the menopause have only begun to be understood. This review summarizes the findings of thirty-four studies of human brain function, including functional magnetic resonance imaging, positron and single-photon computed emission tomography studies, in peri- and postmenopausal women treated with estrogen, or estrogen-progestagen replacement therapy. Seven studies using gonadotropin-releasing hormone agonist intervention as a model of hormonal withdrawal are also included. Cognitive paradigms are employed by the majority of studies evaluating the effect of unopposed estrogen or estrogen-progestagen treatment on peri- and postmenopausal women’s brain. In randomized-controlled trials, estrogen treatment enhances activation of fronto-cingulate regions during cognitive functioning, though in many cases no difference in cognitive performance was present. Progestagens seems to counteract the effects of estrogens. Findings on cognitive functioning during acute ovarian hormone withdrawal suggest a decrease in activation of the inferior frontal gyrus, thus essentially corroborating the findings in postmenopausal women. Studies of the cholinergic and serotonergic systems indicate these systems as biological mediators of hormonal influences on the brain. More, hormonal replacement appears to increase cerebral blood flow in cortical regions. On the other hand, studies on emotion processing in postmenopausal women are lacking. These results call for well-powered randomized-controlled multi-modal prospective neuroimaging studies as well as investigation on the related molecular mechanisms of effects of menopausal hormonal variations in the brain.
... Estrogen has been shown to affect the cognitive performance of both pre-and post-menopausal women. Generally, higher estrogen levels can enhance performance on tasks involving verbal (Morgan et al., 1996;Wolf et al., 1999) and working memory (Epperson et al., 2012;Grigorova et al., 2006;Lacreuse et al., 2002) as well as executive function (Ghidoni et al., 2006;Wegesin and Stern, 2007). On the contrary, the reduction of estrogen that accompanies natural menopause has been associated with reductions in cognitive function (Ahles and Saykin, 2007). ...
Article
The selective estrogen receptor modulator tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer. Although TAM can bind to estrogen receptors in the nervous system, it is unknown whether it acts as an estrogen agonist or antagonist in the human brain. Several studies have reported the negative effects of TAM on cognitive function; however, its effects on decision-making function have not been previously explored. The present study aimed to investigate the decision-making function under ambiguity and risk in breast cancer patients treated with TAM. Participants included breast cancer patients taking TAM (TAM, N = 47) and breast cancer patients not taking TAM (non-TAM, N = 45) as well as their matched healthy controls (HC, N = 50). All participants were given the Iowa Gambling Task (IGT) to assess their decision-making under conditions involving ambiguity, the Game of Dice Task (GDT) to assess their decision-making under conditions involving risk, and a battery of neuropsychological tests. Our results indicated that patients in the TAM group were significantly impaired as assessed by both the IGT and GDT and performed significantly worse on some aspects of various tasks involving memory and information processing. Furthermore, we found that decreased performance on verbal memory testing significantly correlated with IGT performance, and executive dysfunction was associated with poor GDT performance in breast cancer patients undergoing TAM treatment. This study demonstrates that breast cancer patients taking TAM have several decision-making impairments. These findings may support the idea that TAM resulting in cognitive changes plays an antagonistic role in the areas of the brain where estrogen receptors are present, including the prefrontal cortex, hippocampus and amygdala.
... Furthermore, recent research has elucidated cognitive and physiological effects of Gnrh [19][20][21]. Results from mice and human studies of both sexes indicate that modulation of Gnrh and its receptor by use of a Gnrh analog (Gnrh-a) may lead to significant changes in cognitive functions [19,22,23]. ...
Article
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Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.
... It is clear that oestrogen has an important role in cognitive functioning (Sherwin, 2012) but few studies have examined the effect of adjuvant endocrine therapy for breast cancer on cognitive function (Phillips et al, 2010(Phillips et al, , 2011aSchilder et al, 2010;Ganz et al, 2014) and none has assessed the impact of OFS. OFS results in very-low circulating oestrogen levels and some (Varney et al, 1993;Grigorova et al, 2006;Craig et al, 2007), but not all (Owens et al, 2002;Schmidt et al, 2013) data from non-oncological settings suggest that OFS with gonadotropin-releasing hormone agonists (GnRH) agents impair cognition and that this impairment can be reversed with add-back oestrogen (Sherwin and Tulandi, 1996). It has also been reported that surgical menopause adversely affects cognition (Rocca et al, 2007;Ryan et al, 2014). ...
Article
Background: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. Methods: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. Results: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. Conclusions: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.British Journal of Cancer advance online publication 19 April 2016; doi:10.1038/bjc.2016.71 www.bjcancer.com.
... Jovanovic et al. (2008) found modifi ed levels of the serotonin 1A receptor and SERT binding in women ' s brains in comparison with men, suggesting gender diff erences in the functioning of the serotonin system and confi rming the results of other studies (Frey et al. 2010). Th ere are also some studies that have identifi ed diff erences in working memory between the genders, thought to be due to steroid hormones (Janowsky et al. 2000;Grigorova et al. 2006), therefore the occurrence of a higher neuroticism score in females in the present study is not surprising. ...
Article
Objectives: Neuroticism is an important personality trait that is often associated with mental disorders. It has been reported that lower levels of neuroticism are associated with better cognitive function later in life; however, the concurrent association is unclear. Methods: A total of 184 healthy participants, 84 males and 100 females, completed the Wechsler Memory Scale-Revised version and the 24-item neuroticism subscale of the Maudsley personality inventory. Results: The neuroticism score was found to be positively associated with verbal memory, general memory, and delayed recall, particularly among healthy females, independent of the effect of age. Conclusion: The mechanisms of this association remain to be elucidated. Clinicians should pay additional attention to this phenomenon.
... This effect of estrogens on postmenopausal cognitive ability has also been illustrated in rhesus macaques (Rapp et al., 2003). Finally, administration of GnRH to suppress ovarian function resulted in a decrease in activity within the prefrontal cortex, a decrease in memory performance, and a decrease in quality of mood (Craig et al., 2007;Grigorova et al., 2006). Further research is required to clarify the relationship between the prefrontal cortex and estrogens in hormonedependent mood disorders. ...
... • Androgen suppression appears to cause some cognitive impairment in both males and females [48][49][50][51][52], However… • The nature of the cognitive loss from aLH-RH drugs remains controversial (e.g., [53][54][55][56][57][58]). ...
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LAY ABSTRACT Transdermal estradiol (tE2), in the form of patches or topical gel, can provide the same level of
... To gain an understanding of the hormonal mechanisms that might underlie sex differences in cognitive functions, studies have investigated the modulatory effects of gonadotropin-releasing hormone (GnRH) and its agonist (GnRHa) ( Grigorova et al., 2006;Bryan et al., 2010;Wojniusz et al., 2011) on physiological and cognitive parameters (Skinner et al., 2009;Wojniusz et al., 2011;Evans et al., 2012). GnRH is a decapeptide neurohormone that plays a key role in the reproductive axis, ultimately modulating the release of gonadal steroid hormones. ...
... In parallel, there is now mounting evidence from human neuroimaging studies implicating sex steroids in the regulation of memory circuitry (Duff and Hampson 2000;Sherwin 2003;Grigorova et al. 2006;Dumas et al. 2010;Jacobs and D'Esposito 2011;Epperson et al. 2012;Hampson and Morley 2013;Shanmugan and Epperson 2014). This research builds on the pioneering work of Berman et al. (1997) and Shaywitz et al. (1999), who used pharmacological blockade and hormone replacement techniques to illustrate estradiol and progesterone's influence on regional activity in memory circuitry. ...
Article
Converging preclinical and human evidence indicates that the decline in ovarian estradiol production during the menopausal transition may play a mechanistic role in the neuronal changes that occur early in the aging process. Here, we present findings from a population-based fMRI study characterizing regional and network-level differences in working memory (WM) circuitry in midlife men and women (N=142; age range 46-53), as a function of sex and reproductive stage. Reproductive histories and hormonal evaluations were used to determine menopausal status. Participants performed a verbal WM task during fMRI scanning. Results revealed robust differences in task-evoked responses in dorsolateral prefrontal cortex and hippocampus as a function of women’s reproductive stage, despite minimal variance in chronological age. Sex differences in regional activity and functional connectivity that were pronounced between men and premenopausal women were diminished for postmenopausal women. Critically, analyzing data without regard to sex or reproductive status obscured group differences in the circuit-level neural strategies associated with successful working-memory performance. These findings underscore the importance of reproductive age and hormonal status, over and above chronological age, for understanding sex differences in the aging of memory circuitry. Further, these findings suggest that early changes in working memory circuitry are evident decades before the age-range typically targeted in cognitive aging studies.
... Also, men tend to show bilateral activation or right-sided dominance during the completion of this task, whereas women predominantly show left-sided activation (12). There are indications that menstrual cycle pattern-dependent E 2 levels relate to working memory (13,14). It is, however, unclear whether changes in androgen levels affect working memory processes as well (15)(16)(17). ...
Article
Objective: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). Design: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. Setting: Department of reproductive medicine, university medical center. Patient(s): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. Intervention(s): Antiandrogenic hormone treatment. Main outcome measure(s): Functional MRI response during a working memory task. Result(s): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. Conclusion(s): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. Clinical trial registration number: NTR2493.
... [15] These might be resulted from their awareness of their inability to control the circumstances. [9] Efforts to conceal infertility and efforts to get treatment as a result of concerns about being labeled as "infertile," [15,16] are common among Iranian couples. This, by itself, could increase the level of anxiety among women when treatment starts. ...
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Introduction: The process of assisted reproductive treatment is a stressful situation in the treatment of infertile couples and it would harm the mental health of women. Fertile women who started infertility treatment due to male factor infertility have reported to experience less stress and depression than other women before the assisted reproductive process but considering the cultural and social factors and also the etiology of the assisted reproductive process, it could affect the metal health of these women. Therefore, this study was conducted to evaluate the mental health of fertile women who undergo assisted reproductive treatment due to male factor infertility. Materials and methods: This study was a prospective study on 70 fertile women who underwent assisted reproductive treatment due to male factor infertility. The exclusion criterion was to stop super ovulation induction. To assess mental health, anxiety and depression dimensions of the general health questionnaire were used. Before starting ovulation induction and after oocyte harvesting, the general health questionnaire was filled by women who were under treatment. Data were analyzed using multi-variable linear regression, paired t-test, and Chi-square. Results: The results showed that the mean score of depression and anxiety before ovulation induction and after oocyte harvesting were not significantly different; but the rate of mental health disorder in the depression dimension was significantly decreased after oocytes harvesting (31.7% vs. 39.7%). Also, there was a significant relation between the level of anxiety and depression before ovulation induction and after oocyte harvesting (P < 0.05). The anxiety level after oocyte harvesting had a positive and significant correlation with the economic situation (P < 0.05). Conclusion: This study revealed that the process of assisted reproductive treatment does not affect the mental health in fertile women independently, but these women start assisted reproductive process with high levels of depression and anxiety. Therefore, prior to the assisted reproductive treatment mental health consultation is needed.
... The working memory processes includes temporal storage and manipulation of information and it needs multiple processes of cognition such as language, perceptual speed, verbal and visual memory, and planning [14]. Studies have also reported that menstrual cycle pattern dependent E 2 levels relate to working memory [15,16], but it was not clear that whether changes in androgen level will affect working processes as well [17][18][19]. The present study aimed to evaluate the hearing and cognition in cases with polycystic ovarian syndrome using conventional audiometry, extended high frequency audiometry and auditory working memory tasks. ...
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Objectives: The present study assessed the hearing and auditory working memory in women with polycystic ovarian syndrome (PCOS). Study Design: Standard group comparison. Materials and Methods: A total of 20 female participants were included in the study and were divided into two groups. Group-1 included ten women diagnosed with PCOS, under ultrasound examination and hyperandrogenism was confirmed through hormonal analysis. Group-2 included ten healthy women, with no evidence of hyperandrogenism and normal menstrual cycles. Routine pure tone audiometry was done in the frequency range of 250 Hz to 8000 Hz and extended high frequency hearing thresholds from 9000 Hz to 16,000 Hz, was also obtained. Auditory working memory was assessed through digit span and digit sequencing tasks. Results: The results revealed that the extended high frequency audiometry threshold was significantly poorer for PCOS group compared to the normal group for 9000 Hz (F1, 34=9.444, p<0.05), 10000 Hz (F1, 34=6.120, p<0.05), 11200 Hz (F1, 34=9.211, p<0.05), 12500 Hz (F1, 34=12.651, p<0.05), 14000 Hz (F1, 34=41.342, p<0.05), 16000 Hz (F1, 34=12.230, p<0.05). Comparison across various auditory working memory tasks showed that the PCOS group performed significantly poorer on backward digit task (Z=-1.996, p<0.05), ascending digit task (Z=-1.989, p<0.05) and descending digit task (Z=-3.198, p<0.01). Conclusion: These findings suggest that the high frequency sensitivity and working memory is affected in subjects with PCOS compared to the normal group. The study highlights the importance of early identification of hearing loss in PCOS group and the importance of auditory working memory screening in women with PCOS.
... Another example of the therapeutic possibilities of TIB on mood can be seen in women treated with gonadotropin-releasing hormone inhibitors for the management of uterine leiomyomas. It has been shown that these women exhibit decreases in cognitive status and affective disorders with this treatment [128], effects that may be reversed with the addition of estrogenic therapies [129] or TIB [130]. This means that TIB could confer benefits on mood and cognitive performance, but several variables can affect these observations and more investigations with a focus on specific TIB metabolization and receptor activation in brain regions that regulate mood and cognition must be conducted. ...
Article
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Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB’s actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties.
... Although the influence of estradiol on the specific types of cognitive abilities including working memory has been consistently reported [18][19][20][21] , the exact mechanism has not been well established. According to some previous studies, estrogen might play a role as a mediator, inducing neural changes in several brain areas 31,32 . ...
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Postpartum working memory decline has been investigated mostly with neuropsychological tests, but neural evidence is almost unknown. Here we investigated task-related neural alterations during working memory task (n-back) and intrinsic alterations during resting-state (rs) in postpartum women using functional MRI (fMRI). Behaviorally, postpartum women showed comparable working memory performances to the controls although there was a tendency of prolonged response time. fMRI analysis results showed hyper-activation in regions belong to the task positive network (TPN) during the task and hypo-rsfMRI values in the default mode network (DMN) regions during rest in postpartum women. Based on these results, we performed network connectivity analysis using nodes of the TPN and DMN. As a result, the DMN showed a tendency of decreased connectivity in postpartum women during the working memory process compared to the controls. Our results suggest that postpartum women might have functional alterations in the DMN, and that hyper-activation in the TPN during a task might be a compensatory mechanism to maintain working memory performance in postpartum women.
... Makovski et al. explored the role of the visual cortex in retaining visual working memory information using transcranial direct current stimulation reporting that the occipital cortex are involved in working memory consolidation (35). Especially, working memory is one of the main cognitive side effects of GnRHa (36,37). Increased homotopic connectivity within the occipital cortex which influence the development of girls' working memory in GnRHa treated ICPP may be the crucial neural mechanism of GnRHa's working memory dysfunction. ...
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Purpose: The pubertal growth suppressive effects of gonadotropin hormone releasing hormone agonists (GnRHa) are well-known, although it remains unclear if long-term GnRHa treatment influences the brain function of treated children. The present study investigated the differences in the homotopic resting-state functional connectivity patterns in girls with idiopathic central precocious puberty (ICPP) with and without GnRHa treatment using voxel-mirrored homotopic connectivity (VMHC). Methods: Eighteen girls with ICPP who underwent 12 months of GnRHa treatment, 40 treatment-naïve girls with ICPP, and 19 age-matched girls with premature thelarche underwent resting-state functional magnetic resonance imaging using a 3T MRI. VMHC method was performed to explore the differences in the resting-state interhemispheric functional connectivity. The levels of serum pubertal hormones, including luteinizing hormone (LH), follicular-stimulating hormone, and estradiol, were assessed. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales, and VMHC values of different brain regions were performed with the data of the GnRHa treated group. Results: Significant decreases in VMHC of the lingual, calcarine, superior temporal, and middle frontal gyri were identified in the untreated group, compared with the control group. Medicated patients showed decreased VMHC in the superior temporal gyrus, when compared with the controls. Compared to the unmedicated group, the medicated group showed a significant increase in VMHC in the calcarine and middle occipital gyrus. Moreover, a positive correlation was observed between basal LH levels and VMHC of the middle occipital gyrus in medicated patients. Conclusions: These findings indicate that long-term treatment with GnRHa was associated with increased interhemispheric functional connectivity within several areas responsible for memory and visual process in patients with ICPP. Higher interhemispheric functional connectivity in the middle occipital gyrus was related to higher basal LH production in the girls who underwent treatment. The present study adds to the growing body of research associated with the effects of GnRHa on brain function.
... Extensive animal studies have revealed the effects of estrogen on the structural and synaptic plasticity of hippocampus (Foy et al., 2008;Hara et al., 2012;Liu et al., 2008;MCEWEN, 2002;Morrison et al., 2006;Woolley and McEwen, 1993;Woolley et al., 1990) and the prefrontal cortex (Dumitriu et al., 2010;Hao et al., 2006;Morrison et al., 2006;Rapp et al., 2003;. Human studies have also implicated the effects of estradiol on the memory circuitry (Barth et al., 2016;Duff and Hampson, 2000;Dumas et al., 2010;Grigorova et al., 2006;Shaywitz et al., 1999). In the current study, a data-driven (principal component analysis) method was used to select the hippocampal voxels most associated with encoding during the face-name associative memory task. ...
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Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65–93 years old). We found that men and women showed different associations between Aβ load and hippocampal functional connectivity. During associative memory encoding, in men greater Aβ burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aβ burden. For resting-state data, the interaction of gender × Aβ on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest–based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aβ load in men and was negatively correlated with Aβ load in women. The observed Aβ-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women.
... However, effects on WM have also been reported in younger women. Reduction in endogenous estradiol activity by drugs that inhibit estrogen synthesis (or by tamoxifen, a drug that acts at the estrogen receptor) is reported to diminish N-back performance [31,32], and the consumption of high-dose soy isoflavones containing phytoestrogens led to improved WM during a low-estrogen phase of the menstrual cycle [33]. Conversely, the high concentrations of 17βestradiol that characterize the preovulatory or luteal phases of the natural ovarian cycle are associated with modestly improved WM performance on the SPWM [23], compared with the menstrual phase where estradiol production is at its lowest ebb. ...
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Purpose of Review Working memory (WM) is a key process that is integral to many complex cognitive tasks, and it declines significantly with advancing age. This review will survey recent evidence supporting the idea that the functioning of the WM system in women is modulated by circulating estrogens. Recent Findings In postmenopausal women, increased estrogen concentrations may be associated with improved WM function, which is evident on WM tasks that have a high cognitive load or significant manipulation demands. Experimental studies in rhesus monkeys and human neuroimaging studies support a prefrontal locus for these effects. Defining the basic neurochemical or cellular mechanisms that underlie the ability of estrogens to regulate WM is a topic of current research in both human and animal investigations. Summary An emerging body of work suggests that frontal executive elements of the WM system are influenced by the circulating estrogen concentrations currently available to the CNS and that the effects are region-specific within the frontal cortex. These findings have implications for women’s brain health and cognitive aging.
... Also, it was reported that the human cerebral cortex may contain low levels of GnRH [164] and that exogenous GnRH can access the brain [165]. There is evidence, in women, that chronic administration of leuprolide acetate (LA), a GnRH agonist, alters the neural circuitry underlying performance of visual working memory [159,160], but these studies cannot discriminate between direct LA effects or the induced hypo-oestrogenic environment. ...
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This brief review of the neurological effects of growth hormone (GH) and gonadotropin-releasing hormone (GnRH) in the brain, particularly in the cerebral cortex, hypothalamus, hippocampus, cerebellum, spinal cord, neural retina, and brain tumors, summarizes recent information about their therapeutic potential as treatments for different neuropathologies and neurodegenerative processes. The effect of GH and GnRH (by independent administration) has been associated with beneficial impacts in patients with brain trauma and spinal cord injuries. Both GH and GnRH have demonstrated potent neurotrophic, neuroprotective, and neuroregenerative action. Positive behavioral and cognitive effects are also associated with GH and GnRH administration. Increasing evidence suggests the possibility of a multifactorial therapy that includes both GH and GnRH.
... This is consistent with previous results. It has been widely accepted that estrogen has neuroprotective effects on cognitive functions including working memory, verbal memory, and prospective memory in postmenopausal 14,32 as well as premenopausal 33,34 women. Estrogen has been suggested to be associated with cognitive function via modulation of brain activation 35 and regional cerebral blood flow 13,36 in particular regions including the inferior frontal gyrus, ACC, hippocampus, and IPL which overlap with the regions found in our study. ...
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Prospective memory (PM) refers to the ability to remember to execute an intended action in the future. For successful PM performance, both top-down strategic monitoring and bottom-up spontaneous retrieval processes need to be appropriately recruited. We assessed PM performance and used fMRI to discover relevant neural correlates and possible predictors for PM performance in 25 postpartum and 26 nulliparous age- and education-matched women. Postpartum women showed decreased PM performance, a higher number of nocturnal awakenings, and lower estradiol level. The postpartum women had decreased functional connectivity (FC) in the right hippocampus and ventral frontoparietal networks (FPN) during retrieval-dominant PM trials relative to maintenance-dominant ongoing trials in the PM block. On multivariate analyses, decreased FC between the right hippocampus and ventral FPN and a higher number of nocturnal awakenings were independent predictors for poor PM performance after adjusting for age, education, estradiol level, and depressive symptoms. On mediation analyses, the estradiol level was found to have an indirect effect on PM accuracy via altered FC as a mediator. This suggests that decreased FC within the spontaneous retrieval-related regions including the right hippocampus and ventral FPN, disrupted sleep rhythms, and decreased estradiol level may contribute to poor PM performance in postpartum women.
Article
This study investigated the actions of blocking the GnRH receptor using a specific agonist on the response of male and female sheep to a novel object placed in their pen. The study is part of a series performed on 46 same sex twin animals. One of the pair received a subcutaneous implant of the GnRH agonist Goserelin acetate every four weeks while the other remained untreated. Implantation began immediately prior to puberty; at 8 weeks in the males and 28 weeks in the females (as timing of puberty is sex specific). To determine the effects of agonist treatment on the reproductive axis blood samples were collected for measurement of testosterone in the males and progesterone in the females. In addition the volume of the scrotum was determined. The present study aimed to determine whether there are sexually differentiated behavioural responses to a novel object at different stages of brain development (8, 28 and 48 weeks of age) and whether these responses are altered by GnRHa treatment. Approach behaviour towards and interactions with the novel object were monitored as was the number of vocalisations per unit time during the test period. GnRHa treatment suppressed testosterone concentrations and testicular growth in the males and progesterone release in the females. Sheep vocalised significantly more prior to weaning (8 weeks of age) than post weaning (28 and 48 weeks of age) suggesting stress on separation from their dams. Our current study shows that males are more likely to leave their conspecifics to approach a novel object than females. As this behaviour was not altered by suppression of the reproductive axis we suggest that, although sex differences are more obviously expressed in the phenotype after puberty, these may be developed during adolescence but not primarily altered during puberty by sex hormones.
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Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination.
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Introduction: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination. Methodology: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV). Results: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk.
Article
Although there is evidence from randomized controlled trials that estrogen therapy protects against aspects of cognitive decline that occur with normal aging in women, findings from the Women's Health Initiative Memory Study and from some cross-sectional and longitudinal studies failed to find neuroprotective effects of estrogen in older women. There is growing empirical support for the critical-period hypothesis, formulated in the attempt to resolve these discrepancies. It holds that estrogen therapy has protective effects on verbal memory and on working memory only when it is initiated closely in time to menopause, whereas starting treatment many years following menopause does not protect and may even be harmful. Supporting evidence for this hypothesis from basic neuroscience and from animal and human studies is evaluated for its ability to explain the inconsistencies and to describe the conditions under which estrogen may protect cognitive function in aging women.
Article
Tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer and exerts agonistic/antagonistic effects on estrogen receptors throughout the body. Accumulating evidence has revealed that breast cancer patients receiving TAM manifest cognitive dysfunction. However, whether these patients have a global attention deficit or a more selective impairment of specific attention networks remains unknown. In the present study, we sought to explore the attention function of premenopausal women with hormone receptor-positive breast cancer treated with TAM using the attention network test (ANT). The subjects included breast cancer patients receiving TAM (TAM, N = 43), breast cancer patients not receiving TAM (non-TAM, N = 41), and matched healthy controls (HC, N = 46). The subjects completed the ANT and neuropsychological tests, which measure three independent attention networks and executive function performance, respectively. Our results indicated that patients in the TAM group had significant deficits in their executive control component but not in the alerting or orienting components. Moreover, the patients showed poor executive function performance in the neuropsychological tests. Additionally, in the TAM group, significant correlations were found between the decreased efficiency of the executive control component and their reduced performance in executive function tests. This study demonstrates that premenopausal women with hormone receptor-positive breast cancer treated with TAM have impairment of the executive attention network and that this impairment was associated with differences in executive function performance.
Article
Estrogen has been proposed to exert a regulatory influence on the working memory system via actions in the female prefrontal cortex. Tests of this hypothesis have been limited almost exclusively to postmenopausal women and pharmacological interventions. We explored whether estradiol discernibly influences working memory within the natural range of variation in concentrations characteristic of the menstrual cycle. The performance of healthy women (n=39) not using hormonal contraceptives, and a control group of age- and education-matched men (n=31), was compared on a spatial working memory task. Cognitive testing was done blind to ovarian status. Women were retrospectively classified into low- or high-estradiol groups based on the results of radioimmunoassays of saliva collected immediately before and after the cognitive testing. Women with higher levels of circulating estradiol made significantly fewer errors on the working memory task than women tested under low estradiol. Pearson's correlations showed that the level of salivary estradiol but not progesterone was correlated inversely with the number of working memory errors produced. Women tested at high levels of circulating estradiol tended to be more accurate than men. Superior performance by the high estradiol group was seen on the working memory task but not on two control tasks, indicating selectivity of the effects. Consistent with previous studies of postmenopausal women, higher levels of circulating estradiol were associated with better working memory performance. These results add further support to the hypothesis that the working memory system is modulated by estradiol in women, and show that the effects can be observed under non-pharmacological conditions.
Article
Background The combined oral contraceptive pill (OC), containing synthetic estrogens and progestins, is used by millions of women worldwide, yet little is known about its effects on cognition or on psychiatric disorders. The progestin component of OCs determines their androgenicity, i.e. whether the OC has androgen binding components with masculinising effects or antiandrogenic components with feminising effects. Objective The present review discusses the literature surrounding OC use and cognition in healthy women. Given the important role that sex hormones play in psychiatric disorders, we also consider the influence of OCs on symptoms of schizophrenia, post-traumatic stress disorder, depression, bipolar disorder, anxiety disorders and indirectly, sleep quality. Results Research has shown that while there are no differences between OC users and non-users, androgenic OCs enhance visuospatial ability and anti-androgenic OCs enhance verbal fluency. Little is known about OCs effects on other cognitive domains, such as memory and executive function. There is little research examining OC use in schizophrenia, post-traumatic stress disorder, bipolar disorder and anxiety disorders. There is some evidence that OC use is associated with depression, however the exact causality of this association remains to be verified. Conclusion We maintain that future studies need to address several methodological limitations, such as separating OCs based on androgenicity to avoid the masking effects that occur when various OCs are considered as one group. As this review highlights several significant effects of OC use on the brain, the implications of OC use needs to be considered in future research.
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Aim: To investigate the role of sex hormones in the modulation of specific cognitive functions across the menstrual cycle of young healthy women, and to apply improved study design by addressing limitations recognized in previous studies. Methods: A homogenous group of 16 young healthy women, with no history of health problems related to menstrual cycle, major psychiatric and neurological disorders or addictions was included in study. All participants were medical students of similar age (21.56 ± 0.15 year). They were subjected to various cognitive tasks at three different phases of the menstrual cycle: early follicular phase, proven ovulatory phase and mid-luteal phase. Special concern was taken to validate blood hormone levels and to determine preovulatory luteinizing hormone (LH)-peak. Results: Analysis of blood hormone levels confirmed that the test sessions were performed at appropriate time points. Most women were presented with the above average results on utilized cognitive tasks, with no significant changes in immediate memory, working memory, delayed recall, verbal learning, delayed verbal learning or verbal fluency in any phase of the menstrual cycle. In addition, test results did not correlate to measured hormone levels. Conclusions: The results suggest that changes in estrogen and progesterone levels during each menstrual cycle did not affect women's everyday functioning to any significant extent.
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Sex hormones have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. Here we review the evidence from animal experiments and human studies reporting interactions between sex hormones and the dominant neurotransmitters, such as serotonin, dopamine, GABA and glutamate. We provide an overview of accumulating data during physiological and pathological conditions and discuss currently conceptualized theories on how sex hormones potentially trigger neuroplasticity changes through these four neurochemical systems. Many brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. As the hippocampus is of particular relevance in the context of mediating structural plasticity in the adult brain, we put particular emphasis on what evidence could be gathered thus far that links differences in behavior, neurochemical patterns and hippocampal structure to a changing hormonal environment. Finally, we discuss how physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo.
Article
Premature ovarian insufficiency (POI) involves loss of ovarian function before age 40. POI has been associated with neurological dysfunction and an increased risk of dementia, perhaps due to depletion in estrogen levels. The present review discusses the effects of POI caused by genetic disorder, natural premature menopause, surgical menopause, breast cancer treatment and gonadotropin-releasing hormone (GnRH) agonist treatment. Overall, data suggest an increased risk of neurological disorder where POI is due to premature menopause or induced from surgery. This increased risk appears to be most apparent on domains of global cognitive and verbal memory tests. Where POI is caused by genetic disorder, observed cognitive deficiencies may be more likely to have a genetic basis rather than being due to the effects of sex steroids on the brain. Findings related to loss of cognitive function after chemotherapy or GnRH treatments are mixed. There are also discrepant data related to use of hormone therapy after POI (particularly after surgical menopause). After surgery, hormone treatment appears to be most beneficial if initiated close to the average natural age of menopause.
Article
Objective: Few have characterized cognitive changes with age as a function of menopausal stage relative to men, or sex differences in components of memory in early midlife. The study aim was to investigate variation in memory function in early midlife as a function of sex, sex steroid hormones, and reproductive status. Methods: A total of 212 men and women aged 45 to 55 were selected for this cross-sectional study from a prenatal cohort of pregnancies whose mothers were originally recruited in 1959 to 1966. They underwent clinical and cognitive testing and hormonal assessments of menopause status. Multivariate general linear models for multiple memory outcomes were used to test hypotheses controlling for potential confounders. Episodic memory, executive function, semantic processing, and estimated verbal intelligence were assessed. Associative memory and episodic verbal memory were assessed using Face-Name Associative Memory Exam (FNAME) and Selective Reminding Test (SRT), given increased sensitivity to detecting early cognitive decline. Impacts of sex and reproductive stage on performance were tested. Results: Women outperformed men on all memory measures including FNAME (β = -0.30, P < 0.0001) and SRT (β = -0.29, P < 0.0001). Furthermore, premenopausal and perimenopausal women outperformed postmenopausal women on FNAME (initial learning, β= 0.32, P = 0.01) and SRT (recall, β= 2.39, P = 0.02). Across all women, higher estradiol was associated with better SRT performance (recall, β = 1.96, P = 0.01) and marginally associated with FNAME (initial learning, β = 0.19, P = 0.06). Conclusions: This study demonstrated that, in early midlife, women outperformed age-matched men across all memory measures, but sex differences were attenuated for postmenopausal women. Initial learning and memory retrieval were particularly vulnerable, whereas memory consolidation and storage were preserved. Findings underscore the significance of the decline in ovarian estradiol production in midlife and its role in shaping memory function.
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Working memory is responsible for the short-term storage and online manipulation of information necessary for higher cognitive functions, such as language, planning and problem-solving. Traditionally, working memory has been divided into two types of processes: executive control (governing the encoding manipulation and retrieval of information in working memory) and active maintenance (keeping information available 'online'). It has also been proposed that these two types of processes may be subserved by distinct cortical structures, with the prefrontal cortex housing the executive control processes, and more posterior regions housing the content-specific buffers (for example verbal versus visuospatial) responsible for active maintenance. However, studies in non-human primates suggest that dorsolateral regions of the prefrontal cortex may also be involved in active maintenance. We have used functional magnetic resonance imaging to examine brain activation in human subjects during performance of a working memory task. We used the temporal resolution of this technique to examine the dynamics of regional activation, and to show that prefrontal cortex along with parietal cortex appears to play a role in active maintenance.
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There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior. To study this in humans directly, we used H215O positron-emission tomography to measure regional cerebral blood flow (rCBF) in young women during three pharmacologically controlled hormonal conditions spanning 4-5 months: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate (Lupron), Lupron plus estradiol replacement, and Lupron plus progesterone replacement. Estradiol and progesterone were administered in a double-blind cross-over design. On each occasion positron-emission tomography scans were performed during (i) the Wisconsin Card Sorting Test, a neuropsychological test that physiologically activates prefrontal cortex (PFC) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus, and (ii) a no-delay matching-to-sample sensorimotor control task. During treatment with Lupron alone (i.e., with virtual absence of gonadal steroid hormones), there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change. Most strikingly, there was no rCBF increase in PFC. When either progesterone or estrogen was added to the Lupron regimen, there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation. These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans.
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Over the years, a large body of literature has shown that humans display losses in memory with age, but that not all types of memory are affected equally. Similarly, recent evidence from functional neuroimaging experiments has revealed that, depending on the task, older adults can display greater or lesser activity in task-relevant brain areas compared with younger adults. Recent behavioral and neurophysiological experiments are furthering our understanding of the effects of aging on cognition. It appears that some brain changes seen with age may be compensatory.
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The relation between estrogen and cognition among postmenopausal women remains controversial. Also uncertain is whether the proposed association varies between women taking unopposed estrogen and those taking estrogen combined with progestin. To determine whether unopposed estrogen and combined estrogen-progestin use were associated with the rate of cognitive change in a cohort of older, Japanese American, postmenopausal women. A prospective observational study in a population-based cohort of older Japanese Americans (aged > or =65 years) living in King County, Washington. Cognitive performance was measured in 837 women at baseline (1992-1994) and 2-year follow-up (1994-1997) examinations using the 100-point Cognitive Abilities Screening Instrument (CASI). Least squares means general linear models were used to estimate the 2-year rate of cognitive change according to categories of postmenopausal estrogen use. Approximately half of this cohort (n=455) had never used estrogen at any time since menopause, 186 were past users, 132 were current unopposed estrogen users, and 64 were current estrogen-progestin users. The majority of current estrogen users were taking conjugated estrogens, and all women receiving combined therapy were taking medroxyprogesterone acetate. After adjusting for age, education, language spoken at the interview, surgical menopause, and baseline CASI score, women who had never used postmenopausal estrogen improved slightly on the CASI scale (mean adjusted change, 0.79; SEM, 0.19). This change was significantly greater for current unopposed estrogen users (mean adjusted change, 1.68; SEM, 0.36; P=.04) and significantly worse for current estrogen-progestin users (mean adjusted change, -0.41; SEM, 0.50; P =.02) compared with never users. The improvement observed in past users (mean adjusted change, 1.12; SEM, 0.29) was intermediate between the changes for never users and current unopposed estrogen users and not significantly greater than that for never users (P=.35). Our findings support a modest beneficial association between current unopposed estrogen use and the rate of cognitive change. We also observed a modest detrimental association between current estrogen-progestin use and the rate of cognitive change. The clinical significance of these modest differences, however, is uncertain. Data from large, long-term randomized trials are required before applying this information to the clinical setting.
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Context Preclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women. Objective To investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks. Design Randomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998. Setting Community volunteers tested in a hospital setting. Patients Forty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years). Intervention Twenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments. Main Outcome Measures Brain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. Results Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks. Conclusions Estrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.
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Estrogen is thought to have an impact on both psychological well being and cognitive function. The biological basis to this is not fully understood, but may involve estrogen's interactions with central serotonergic (5-HT) systems. Therefore, we studied the effect of long-term estrogen hormone replacement therapy (ERT) on central 5-HT tone in healthy postmenopausal women and made comparisons with young women. Prolactin (PRL) responses to the specific 5-HT releasing and re-uptake inhibiting agent, d-fenfluramine, were measured in three groups of healthy women: 11 young, 11 postmenopausal on long-term ERT, and 11 postmenopausal ERT naı̈ve. PRL responses were significantly decreased in ERT naı̈ve women compared to young healthy women. In contrast, PRL responses were not different between estrogen-treated and young women. Overall, there was a significant relationship between older age and lower PRL responsivity. These results suggest that central 5-HT tone is reduced in healthy postmenopausal women who are ERT naı̈ve, but not in postmenopausal women who have received prolonged estrogen treatment. Estrogen may modulate age-related changes in 5-HT tone. This may partly explain why estrogen can decrease vulnerability to mood disorders and cognitive changes in postmenopausal women.
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The effects of estrogen (E) on memory were assessed in 19 women who required a hysterectomy and bilateral oophorectomy for benign disease. Blood samples were drawn and memory tests were administered before surgery and again after 2 mo of postoperative treatment consisting of either monthly E or placebo (PL) injections. Scores on the immediate and delayed recall of paired-associates stayed at the same level in E-treated women, whereas they decreased significantly pre- to post-operatively in the PL-treated subjects. In the immediate recall of paragraphs, the scores of those given E improved postoperatively compared to baseline; scores remained unchanged in the PL group. No hormonal effects were apparent on the immediate or delayed recall of visual material, delayed recall of paragraphs, or digit span scores. These findings suggest that variations in specific aspects of memory function may occur in surgically menopausal women coincident with changes in plasma estrone and estradiol levels.
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Although depressive symptoms occur in a considerable number of women following a decrease in circulating estrogen levels, a biological correlate of these mood changes has not been identified. In a prospective, double-blind, cross-over investigation of surgically menopausal women, an increase in the number of tritiated imipramine binding sites on platelets and an improvement of mood occurred with estrogen treatment and were reversed when placebo was administered. In vitro studies indicated that this effect was not due to a direct interaction of the steroid with the imipramine binding site at the same concentrations of estradiol induced in the in vivo study. Together with other evidence, these findings suggest that pharmacological but not physiological doses of estrogen can enhance the density of tritiated imipramine binding sites on platelets in women.
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The effect of estrogen and/or androgen replacement therapy on several aspects of cognitive functioning in surgically menopausal women was tested in a prospective, crossover design. Women who received either a combined estrogen-androgen preparation, estrogen alone, or androgen alone had scores on two tests of short-term memory, a test of long-term memory and a test of logical reasoning that were not different during the postoperative treatment phase compared to their preoperative performance. However, oophorectomized women who received placebo had lower scores on all four measures of cognitive functioning postoperatively, coincident with their significantly lower concentrations of plasma estradiol and testosterone. Patients who had a hysterectomy but whose ovaries were retained showed stability both in cognitive performance and in circulating sex steroid concentrations. These findings suggest that the drastic change in endocrine milieu following surgical menopause may have a direct, albeit modest, effect on aspects of cognitive functioning. Possible mechanisms of action of the sex hormones on cognitive functioning in women are discussed.
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The performance of 151 patients with unilateral excisions from either the frontal or the temporal cortex and 60 normal subjects was examined on three motor tasks: (1) simple unimanual tapping; (2) spatially ordered unimanual tapping; and (3) bimanual tapping in which the movements of the two hands were out-of-phase. All patient groups were impaired with both hands on spatially ordered unimanual tapping. In contrast, only those patients with either left or right frontal-lobe lesions performed poorly on the bimanual tapping task. Our findings demonstrate that the frontal cortex plays a critical role in the co-ordination of arm and hand movements, particularly when different movements have to be performed simultaneously.
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The role of mesial temporal-lobe structures in the recall of designs was examined in two experiments. Normal control subjects and patients with right or left temporal lobectomy that included either a large or small excision from the hippocampal zone were tested. In Experiment 1, subjects copied a complex drawing that was presented piecemeal in an illogical order; in Experiment 2 they copied 18 individual designs. In both cases recall was tested 45 min later. Patients with right temporal lobectomy showed deficient recall in both experiments; in Experiment 1 only, patients with a large right hippocampal removal were also significantly impaired compared to those with a small removal.
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The effect of estrogen and/or androgen on mood in surgically menopausal women was investigated with a prospective, double-blind, cross-over design. Oophorectomized women who received either estrogen (E), androgen (A), or a combined estrogen-androgen preparation (E-A) parenterally attained lower depression scores during both treatment phases compared to a placebo group (PL), coincident with their higher plasma estrogen and testosterone levels. When steroids were withdrawn, depression scores of all oophorectomized women were significantly higher than those of a hysterectomized control group with intact ovaries (CON). The A group also had higher hostility scores than the E, PL, and CON groups. These data provide evidence of a covariation between circulating levels of estrogen and testosterone and certain affects in healthy women.
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Currently, the mood states are regarded as monopolar. This study tested in psychiatric subjects for the presence of five bipolar mood states after the influence of extreme response bias had been removed. The affective states hypothesized were: composed vs anxious, agreeable vs hostile, energetic vs fatigued, elated vs depressed, and clear-thinking vs confused. The sample of 303 cases included anxious, depressed and agoraphobic cases. Ratings of the 72 adjectives of the Profile of Mood States were intercorrelated. After extreme response bias score was partialled out the resulting correlations were analyzed by the method of principal components. The five factors isolated clearly support the bipolar nature of mood states postulated.
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The study investigated the neuropsychological status of women with induced hypoestrogenism. An ABA design was employed in which neuropsychological measures were repeated prior to, during, and after induction of hypoestrogenism with leuprolide acetate. The study took place in a medical school affiliated in vitro fertilization clinic. Leuprolide acetate was administered to all subjects as part of in vitro fertilization. Eighteen women receiving in vitro fertilization treatment underwent neuropsychological testing before, during, and after treatment with leuprolide acetate and gonadotrophins. The neuropsychological test battery was selected on the basis of previous patients' symptomatic complaints during periods of hypoestrogenism with leuprolide acetate. Depending upon the tests administered, some individuals showed significant cognitive deficits during therapy particularly in the areas of memory, fine motor coordination, and two-point discrimination. Two of the 18 subjects showed very substantial neuropsychological sequelae including memory gaps and disturbances in a variety of neuropsychological test performances. However, in terms of group statistics, only two-point discrimination and delayed recall memory test performance proved significant. Not all measures were sensitive for the group, as many tests displayed a balance between individuals who showed practice effects and those who showed detrimental effects. For a substantial portion of individuals, hypoestrogenism can result in statistically significant or clinically noteworthy problems with memory, dexterity, and two-point discrimination.
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Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause.
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Studies suggest that estrogen replacement can influence learning and memory processes via effects on cholinergic neurons located in specific regions of the basal forebrain. In the present study, immunocytochemical techniques were used to examine the effects of estrogen on basal forebrain cholinergic neurons as a function of the dose and duration of estrogen treatment. Ovariectomized rats received 2, 10, 25, or 100 microg estradiol every other day for a period of 1, 2, or 4 weeks. Sections through the basal forebrain were then processed for the detection of choline acetyltransferase (ChAT) or the low-affinity nerve growth factor receptor (p75NGFR), and the number of immunoreactive cells in the medial septum (MS), the horizontal limb of the diagonal band of Broca (HDB) and the nucleus basalis magnocellularis (NBM) were counted. The effects of dose and duration of estrogen treatment were evaluated by analysis of variance and individual group means were compared with ovariectomized controls using a two-tailed Dunnets test. Administration of 2, 10, or 25 microg estradiol for 1 week produced a dose-related increase in the number of ChAT-like immunoreactive (IR) cells detected in the MS. Likewise treatment with 10 microg estradiol for 1 week, or with 2 microg estradiol for 2 weeks resulted in a significant increase in the number of ChAT-IR cells detected in the NBM. These effects were not observed following treatment with higher doses of estradiol. Nor were they maintained following repeated administration of estradiol for longer periods of time. In contrast, repeated administration of estradiol for 2 or 4 weeks resulted in significant decreases in the number of p75NGFR-IR cells detected in the MS, with the greatest effects observed following treatment with the higher doses of estradiol for longer periods of time. These findings demonstrate that (1) estrogen replacement produces regionally selective effects on basal forebrain cholinergic neurons which vary as a function of both the dose and duration of estrogen treatment, and (2) estrogen has both short-term and longer-term effects on basal forebrain cholinergic neurons, each of which may contribute to the effects of estrogen on learning and memory process and the development of age- and disease-related cognitive decline.
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Neurocognitive research has focused on monoaminergic influences over broad behavior patterns. For example, dopamine (DA) generally facilitates informational transfer within limbic and cortical networks to promote reward-seeking behavior. Specifically, DA activity in prefrontal cortex modulates the ability for nonhuman primates and humans to perform spatial working memory tasks. Serotonin (5HT) constrains the activity of DA, resulting in an opposing relationship between DA and 5HT with respect to emotional and motor behaviors. A role for 5HT in constraining prefrontally guided spatial working memory (WM) processes in humans has not been empirically demonstrated but is a logical avenue for study if these principles of neurotransmitter activity hold within cortical networks. In this study, normal humans completed a visuospatial WM task under pharmacological challenge with (i) bromocriptine, a DA agonist and (ii) fenfluramine, a serotonin agonist, in a double-blind, repeated-measures, placebo-controlled design. Findings indicate that bromocriptine facilitated spatial delayed, but not immediate, memory performance. Fenfluramine resulted in impaired delayed spatial memory. These effects were not due to nonspecific arousal, attentional, sensorimotor or perceptual changes. These findings suggest that monoaminergic neurotransmitters (DA and 5HT) may interact within cortical networks to modulate the expression of specific cognitive behaviors, particularly effortful processes associated with goal-directed activity.
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Preclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women. To investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks. Randomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998. Community volunteers tested in a hospital setting. Forty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years). Twenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments. Brain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks. Estrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.
Article
Traditional theories of working memory and executive function, when mapped in straightforward ways into the neural domain, yield predictions that are only partly supported by the recent neuroimaging studies. Neuroimaging studies suggest that some constituent functions, such as maintaining information in active form and manipulating it, are not discretely localized in prefrontal regions. Some hypothesized executive processes, such as goal management, have effects in several cortical regions, including posterior regions. Such results suggest a more dynamic and distributed view of the cortical organization of working memory and executive functions.
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In the last ten years, numerous mechanisms by which sex steroids modify cortical function have been described. For example, estrogen replacement improves verbal memory in women, and animal studies have shown effects of estrogen on hippocampal synaptogenesis and function. Little is known about sex steroid effects on other aspects of memory, such as frontal lobe-mediated working memory. We examined the relationships between working memory and sex steroid concentrations and whether sex steroid supplementation would modify age-related loss of working memory in older men and women. Before hormone supplementation, working memory, tested with the Subject Ordered Pointing Test (SOP), was worse in older subjects than younger subjects, and there was no evidence of gender differences at either age. Testosterone supplementation improved working memory in older men, but a similar enhancement of working memory was not found in older women supplemented with estrogen. In men, testosterone and estrogen effects were reciprocal - with better working memory related to a higher testosterone to estrogen ratio. These results suggest that sex steroids can modulate working memory in men and can act as modulators of cognition throughout life.
Article
Recent neurophysiological data suggest that the prefrontal cortex (PFC) may be susceptible to modulation by estrogen. In humans, the PFC mediates a number of cognitive processes that contribute to memory function, particularly working memory. The present study examined whether memory tasks that recruit PFC-dependent information processing might exhibit estrogen sensitivity in women. Performance on several memory tasks, including measures of working memory, was evaluated in three groups of postmenopausal women: (1) women who were tested when taking estrogen only (n = 38, M(age) = 55.1 years), (2) women who were tested when taking estrogen and a progestin concurrently (n = 23, M(age) = 55.9 years), and (3) women who were not taking hormone replacement therapy (n = 35, M(age) = 56.0 years). Estrogen users exhibited significantly better performance on a verbal task and on a spatial task, each with a prominent working memory component, but did not differ from nonusers on control tasks involving simple passive recall. These findings are consistent with the hypothesis that estrogen is active within PFC and is capable of influencing functions dependent on this region. The results of this study raise the possibility that estrogen may play a role in maintaining certain frontal lobe functions in women.
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A computational model was previously developed to investigate the role of parallel basal ganglia-thalamocortical loops in solving tasks that rely on working memory. Different lesions are applied to the model in order to investigate the working memory deficits observed in Parkinson's disease and schizophrenia. The simulations predict that the working memory deficits observed in Parkinson's disease result from a local dysfunction within the brain due to a problem in the disinhibitory process arising from the basal ganglia. They also predict that the working memory deficits observed in schizophrenia involve many cortical and subcortical areas and result from a problem in selecting items in working memory which are stored in basal ganglia-thalamocortical loops. The simulations predict the temporal unfolding of neuronal activity in different brain regions, both in the normal case and in the two disease states. A specific event-related functional magnetic resonance imaging study was elaborated to test some of those predictions.
Article
The hippocampus has long been presumed the primary site of action of estrogens on cognition; and explicit memory is considered the cognitive function most vulnerable to menopausal loss of estrogen. We hypothesize instead that the prefrontal cortex and its neural circuitry are prime mediators of estrogen's role in cognition. We also propose that previously reported menopausal cognitive decline, presumed to be hippocampally mediated, may be secondary to executive dysfunction. We used a cross sectional design to compare the performance of nine menopausal women on hormone replacement therapy (HRT) and 10 menopausal women with no prior exposure to HRT on a battery of neuropsychological tests. The battery was comprised primarily of tests of memory and executive functioning. Executive functioning is mediated by the frontal lobes and encompasses working memory, directed attention, the inhibition of inappropriate responses, cognitive set switching, and behavioral monitoring. Unlike most previous studies, we used a memory measure that yields multiple scores reflecting various problem-solving strategies and error types, thus isolating spared and impaired cognitive processes. Results yielded both qualitative and quantitative evidence for disruption of cognitive processes subserved by the frontal lobes rather than the hippocampus: 1) despite intact free recall on a list-learning task (CVLT), untreated menopausal women were relatively impaired in correctly recognizing words previously learned and distinguishing them from items not on the list (discriminability), 2) untreated women also had difficulty inhibiting inappropriate responses in the form of perseverative errors, and 3) the non-HRT group consistently performed worse on the N-back test of working memory. The prefrontal cortex is critical for intact working memory and estrogen enhances performance on working memory tasks. In conclusion, this study provides preliminary evidence for executive dysfunction in untreated menopausal women as women with HRT outperformed women without HRT on tests requiring directed attention, inhibition of inappropriate responses, and cognitive set switching.
Article
To evaluate the effect of a pharmacologically induced, temporary suppression of ovarian hormones on healthy young women's cognitive functioning. Sixteen healthy women with normal menstrual cycles completed the California Verbal Learning Test, a digit span test, and a verbal fluency test in the follicular phase of a normal menstrual cycle and a second time after four monthly injections of the gonadotropin-releasing hormone (GnRH) agonist. Women were randomly assigned to complete a third testing either after resuming cycles in the follicular phase or after three more injections of the GnRH agonist and while wearing an estradiol patch. The control group consisted of 10 women who were tested three times in the follicular phase of their menstrual cycles. Results showed no change in cognitive functioning across sessions or groups in women with suppressed ovarian function. Women who had the highest levels of menopausal symptoms when taking the GnRH agonist did not have significantly lower cognitive functioning. This study did not find any effect of suppression in ovarian hormones on cognitive performance of young women.
Article
The present study was conducted to identify the localization and possible contribution of the two estrogen receptor (ER) subtypes in the rat brain at postnatal (P) days 3, 7 and 14. Evaluation of the distribution of ERalpha and ERbeta immunoreactive (ir) nuclei did not reveal gender differences at the developmental point times examined. With the exception of the cerebral cortex, the pattern of staining for these ERs was unchanged across the postnatal ages examined. The distribution of ERalpha-ir nuclei was wider than ERbeta-ir during brain development. From P3, ERbeta and ERalpha-ir nuclei were found in different regions of the cerebral cortex, basal forebrain, amygdala, thalamus, hypothalamus, mesencephalon, pons, cerebellum and medulla oblongata. In addition, ERalpha-ir nuclei were exclusively detected in the hippocampal subfields, epithalamus and in several circumventricular organs. ERalpha and ERbeta dual immunofluorescence revealed positive nuclei in the medial part of the bed nucleus of the stria terminalis, periventricular preoptic nucleus and in caudal aspects of the ventrolateral part of the ventromedial hypothalamic nucleus. Although the functional significance of the dual expression of both ERs within the same nuclei remains unknown, it is possible that ERs play different roles in gene regulation within the same cell. The presence of ERs in diverse brain regions through early postnatal periods supports a potential role for estrogens in neural differentiation.
Article
Estrogen protects neurons from a variety of experimental insults in vitro, and is thought to protect from acute and chronic neurodegenerative processes in vivo. Estrogen also enhances higher-level cognitive functions that are centered in the dorsolateral prefrontal cortex (DLPFC) in human and non-human primates. To investigate genomic mechanisms involved in estrogenic effects on the primate brain in vivo, we compared transcription factor mRNA and protein expression in the DLPFC of ovariectomized rhesus monkeys treated with either vehicle or estradiol (E2). c-FOS, E2F1, and general transcription factor IIB (TFIIB) mRNA and protein expression were altered significantly by short-term E2 treatment, as shown by DNA array, in situ hybridization, and immunohistochemical and immunoblot evaluations. C-FOS expression was increased significantly whereas E2F1 and TFIIB levels were decreased in the DLPFC of E2-treated animals. These transcription factors were concentrated in cortical pyramids, as were estrogen receptors alpha and beta. These data indicate that estrogen may have direct as well as indirect effects on neuronal gene expression in the primate prefrontal cortex.
Article
GnRH analogue (GnRH-a) administration induces a significant reduction of cognitive functions in premenopausal women with symptomatic uterine leiomyomas and, notwithstanding the appearance of climacteric-like symptoms, the effectiveness of analogue induces a significant improvement of mood and quality of life. The addition of raloxifene to GnRH-a treatment has no clinical effect on cognition, mood, and quality of life in this sample of women.
Stroop Test – Victoria Version. Neuropsycho-logical Laboratory
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Regard, M., 1981. Stroop Test – Victoria Version. Neuropsycho-logical Laboratory. University of Victoria, Victoria, BC.
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