Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals

Gonadal hormones, particularly estrogens, have been suggested to influence memory and cognitive tasks that show sex differences. Previously, we reported that male-to-female (M-F) transsexuals undergoing estrogen treatment for sex re-assignment scored higher on verbal Paired Associate Learning (PAL) than a transsexual control group awaiting estrogen treatment. The present study used a more robust design to examine further associations between estrogen and cognition. We assessed additional aspects of memory, including visual, spatial, object and location memory, other cognitive abilities that show reliable sex differences, including verbal and visual-spatial abilities, and mood variables that could mediate associations between estrogen and cognition. In addition to comparing groups of individuals on and off estrogen, we used two repeated measures designs (AB and BA). The AB group was tested prior to hormone treatment and then again after treatment had begun; the BA group was tested while on estrogen treatment and then again when hormones had been withdrawn prior to surgery. Few changes in memory or cognition were observed, and changes that were observed were not consistent across study designs. The lack of significant effects did not relate to mood changes or to the sexual orientation of participants. These findings suggest that estrogen treatment associated with sex change for M-F transsexuals has little or no influence on sex-typed aspects of cognition or memory.     

An Investigation of Emotion Recognition and Theory of Mind in People with Chronic Heart Failure

Objectives

Cognitive deficits are common in patients with chronic heart failure (CHF), but no study has investigated whether these deficits extend to social cognition. The present study provided the first empirical assessment of emotion recognition and theory of mind (ToM) in patients with CHF. In addition, it assessed whether each of these social cognitive constructs was associated with more general cognitive impairment.

Methods

A group comparison design was used, with 31 CHF patients compared to 38 demographically matched controls. The Ekman Faces test was used to assess emotion recognition, and the Mind in the Eyes test to measure ToM. Measures assessing global cognition, executive functions, and verbal memory were also administered.

Results

There were no differences between groups on emotion recognition or ToM. The CHF group’s performance was poorer on some executive measures, but memory was relatively preserved. In the CHF group, both emotion recognition performance and ToM ability correlated moderately with global cognition (r = .38, p = .034; r = .49, p = .005, respectively), but not with executive function or verbal memory.

Conclusion

CHF patients with lower cognitive ability were more likely to have difficulty recognizing emotions and inferring the mental states of others. Clinical implications of these findings are discussed.     

Action of estrogens in the aging brain: Dementia and cognitive aging

Background

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.

Scope of review

Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.

Major conclusions

Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.

General significance

Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.     

Effects of Short-Term Cognitive Remediation on Cognitive Dysfunction in Partially or Fully Remitted Individuals with Bipolar Disorder: Results of a Randomised Controlled Trial

Introduction

Cognitive dysfunction is common in bipolar disorder (BD) but is not sufficiently addressed by current treatments. Cognitive remediation (CR) may improve cognitive function in schizophrenia but no randomised controlled trial has investigated this intervention in BD. The present study aimed to investigate the effects of CR on persistent cognitive dysfunction in BD.

Method

Patients with BD in partial remission with cognitive complaints were randomised to 12 weeks group-based CR (n=23) or standard treatment (ST) (n=23). Outcomes were improved verbal memory (primary), sustained attention, executive and psychosocial function (secondary) and additional measures of cognitive and psychosocial function (tertiary). Participants were assessed at baseline and weeks 12 and 26.

Results

Of the 46 randomised participants five dropped out and one was excluded after baseline. CR (n=18) had no effect on primary or secondary measures of cognitive or psychosocial function compared with ST (n=22). However, CR improved subjective sharpness at week 12, and quality of life and verbal fluency at week 26 follow-up (tertiary outcomes). Although the trial turned out to have suboptimal statistical power for the primary outcome analysis, calculation of the 95% confidence interval showed that it was highly unlikely that an increase in sample size would have rendered any beneficial effects of CR vs. ST on the verbal memory.

Conclusions

Short-term group-based CR did not seem to improve overall cognitive or psychosocial function in individuals with BD in full or partial remission. The present findings suggest that that longer-term, more intensive and individualised CR may be necessary to improve cognition in BD.

Trial Registration

ClinicalTrials.gov NCT01457235     

Cognitive effects of olanzapine treatment in schizophrenia

Improvement in some but not all domains of cognition during treatment with the atypical antipsychotic drugs clozapine, quetiapine, olanzapine, and risperidone has been reported in some but not all studies. It has been recently suggested that these reports are an artifact, related to lessening of the impairment due to typical neuroleptic drugs and anticholinergic agents. The purpose of this study was to further test the hypothesis that olanzapine, an atypical antipsychotic drug reported to have anticholinergic properties, improves cognition in patients with schizophrenia, including domains of cognition related closely to work and social function (ie, verbal learning and memory) and that this improvement is independent of improvement in psychopathology. Thirty-four patients with schizophrenia who were partial responders to typical antipsychotic drug treatment were evaluated with a comprehensive neurocognitive battery, including measures of executive functioning; verbal and visual learning and memory; working memory; immediate, selective, and sustained attention; perceptual/motor processing; and motor skills prior to and following treatment with olanzapine for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were switched to olanzapine (average dose 13.4 mg, range 5-20 mg) and reassessed following 6 weeks and 6 months of treatment. Significant improvement was noted in 9 of 19 cognitive tests, including measures of selective attention, verbal learning and memory, and verbal fluency. No cognitive test was worsened by olanzapine treatment. Improvements in the BPRS Total and Positive Symptom Subscale scores were noted. Improvements in verbal learning and memory, sustained attention, and psychomotor tracking were independent of improvement in psychopathology. These data suggest that olanzapine improved some but not all cognitive deficits in schizophrenia, including verbal memory, a cognitive domain impaired by anticholinergic drugs. The basis for the improvement in cognitive scores, which should lead to improvement in role functioning if real, is discussed.     

Schizophrenia and cognitive function

Schizophrenia is often associated with cognitive deficits, particularly within the domains of memory and language. Specific cognitive deficits have recently been linked to psychotic phenomena, including verbal hallucinations and disorganized speech. Impairments of working and semantic memory are primarily due to dysfunction of the frontal cortex, temporal cortex, and hippocampus. Cognitive skills in schizophrenia predict social functioning and may serve as outcome measures in the development of effective treatment strategies.     

Effects of the pharmacologic manipulation of testosterone on cognitive functioning in women with polycystic ovary syndrome: a randomized, placebo-controlled treatment study

In a previous study, we found that women with polycystic ovary syndrome (PCOS), an endocrine disorder characterized by chronic hyperandrogenism, performed more poorly than healthy, matched controls on a number of neuropsychological tests, in particular tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory. This randomized, placebo-controlled trial was undertaken to investigate whether pharmacologic manipulation of free testosterone (free T) levels in women with PCOS might affect their performance on cognitive tests. Nineteen women with PCOS completed a battery of neuropsychological tests before and after 3 months of treatment with either an anti-androgen (cyproterone acetate) plus estrogen or with a placebo. Hormone treatment of women with PCOS caused a significant reduction in their free T levels but did not affect performance on tests visuospatial ability, verbal memory, manual dexterity, or perceptual speed. Women treated with hormone therapy did, however, demonstrate an improvement in their performance on a test of verbal fluency compared to their pre-treatment scores. These findings suggest that changes in free T levels do not have a significant impact on cognitive performance in women with PCOS, although reductions in free T may be beneficial for verbal fluency.     

Advanced breast cancer updates on anastrozole versus tamoxifen

Results from two studies, the North American trial and the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) trial carried out in Europe/rest of the world comparing ‘Arimidex’ (anastrozole) 1 mg with tamoxifen 20 mg for treatment of advanced breast cancer in postmenopausal women, have previously been reported individually and as a prospectively combined analysis. For the combined analysis, at a median follow-up of 18.2 months anastrozole was shown to be superior to tamoxifen in terms of time to progression (TTP; P=0.022) in the hormone receptor-positive subgroup. Both treatments were well tolerated; anastrozole was associated with significantly fewer thromboembolic events (P=0.043) and fewer reports of vaginal bleeding. The survival analyses and safety update in the overall population and in the hormone receptor-positive subgroup from the combined data are now available. At a median follow-up of 43 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. At the cut-off date, 2-year mortality rates were 31.7 and 32.5% with anastrozole and tamoxifen, respectively, in the overall population. Median time to death (TTD) was similar for both treatments (39 months versus 40 months, respectively; hazard ratio (HR) 0.97, lower 95% confidence limit (CL) 0.84). Similar findings were reported in the hormone receptor-positive population. With longer follow-up, both anastrozole and tamoxifen remained well tolerated. Sequencing data showed that patients crossed from anastrozole to tamoxifen or tamoxifen to anastrozole are similar regarding efficacy. In conclusion, these TTP, survival and tolerability data support the use of anastrozole as a first-line therapy of choice in postmenopausal women with advanced breast cancer.     

Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men

Relatively few studies have investigated the relationship between endogenous sex steroid levels and cognition in older people and the reported results have been inconsistent. A number of experimental hormone replacement studies have suggested that estrogen replacement in older women enhances cognition, especially verbal memory. In contrast, little research has been done focusing on men. In the current study the association between endogenous sex steroids (estradiol and testosterone) and cognition was investigated in 38 healthy older women (mean age 68 years) and 30 healthy older men (mean age 69 years). Five cognitive tests measuring verbal memory, spatial memory, verbal fluency, mental rotation, and susceptibility to interference were administered. Results revealed that in women higher estradiol levels as well as testosterone levels were associated with better verbal memory (paired associates and estradiol; r =.38, P < 0.05; paired associates and testosterone; r =.33, P < 0.05;). Moreover estradiol, but not testosterone was associated with less susceptibility to interference (Stroop color word test; r = -0.34, P < 0.05). In men the only significant association was a negative correlation between testosterone and verbal fluency (r = -0.38, P < 0.05). The associations observed in this small study support the notion that estradiol is protecting verbal memory and possibly also frontal lobe mediated functions in older women. In contrast to the positive findings in women endogenous sex steroids do not appear to be closely linked to better cognition in older men.     

Sexual Differentiation of Cognitive Abilities in Women Exposed to Diethylstilbestrol (DES) Prenatally

In nonhuman animals, prenatal exposure to androgens or estrogens enhances development of male-typical characteristics (masculinizes) and impairs development of female-typical characteristics (defeminizes). We investigated the hypothesis that prenatal exposure to the synthetic estrogen, diethylstilbestrol (DES), similarly masculinizes or defeminizes cognitive development in women. Forty-two DES-exposed women and 26 of their unexposed sisters were studied. No group differences were seen for abilities at which females excel on average (verbal fluency, perceptual speed and accuracy, and associative memory), for abilities at which males excel on average (visuospatial abilities), or for abilities that do not show sex differences (vocabulary, nonverbal intelligence). The time of prenatal exposure to DES correlated with visuospatial performance with later exposure associated with better performance. However, the subgroup of women exposed to DES late in gestation did not differ from unexposed women on these measures. Results support the conclusion that prenatal exposure to DES has little or no influence on cognitive development in women. However, they do not preclude other types of early hormonal influences on human cognition, such as prenatal influences of androgen or influences of androgens or estrogens during the early postnatal period.     

The aromatase inhibitor letrozole in advanced breast cancer: Effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P = 0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P = 0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P = 0.077) and for the time × dose interaction (P = 0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.     

'Arimidex' (anastrozole) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer--efficacy overview

ATAC, a randomized, double-blind trial, compared tamoxifen (20 mg) with anastrozole (‘Arimidex’) (1 mg) alone, and the combination of anastrozole plus tamoxifen (combination), as adjuvant endocrine treatment for postmenopausal patients with early breast cancer. Patients with operable invasive breast cancer following completion of primary therapy, who were candidates to receive adjuvant endocrine therapy, were eligible for this study. Primary endpoints were disease-free survival (DFS) and tolerability. Other endpoints included time to recurrence (TTR: censoring non-breast cancer deaths before recurrence) and the incidence of contralateral breast cancer. A total of 9366 patients were included in this study (N=3125, 3116 and 3125 for anastrozole, tamoxifen and the combination, respectively). Median duration of therapy was 30.7 months and median follow-up was 33.3 months. The total numbers of events were 317, 379 and 383 for anastrozole, tamoxifen and the combination, respectively. DFS was significantly improved in the overall population for anastrozole versus tamoxifen (hazard ratio (HR)=0.81, 95% confidence interval (CI) (0.71–0.96), P=0.013). Anastrozole showed improved TTR compared with tamoxifen (HR=0.79, CI (0.67–0.94), P=0.008), which improved even further in the ER+ and/or PR+ subgroup (HR=0.73, CI (0.59–0.90), P=0.003). The incidences of hot flushes, thromboembolic events, ischaemic cerebrovascular events, vaginal bleeding/discharge and endometrial cancer were significantly reduced with anastrozole compared with tamoxifen (P<0.03 for all). Musculoskeletal disorders and fractures were significantly reduced in patients receiving tamoxifen compared with those on anastrozole (P<0.03 for both). No increase in hip fractures was seen for anastrozole versus tamoxifen (11 versus 13, respectively). Combination treatment was equivalent to tamoxifen in terms of both efficacy and tolerability. Anastrozole showed superior efficacy to tamoxifen for DFS, TTR and contralateral breast cancer. Early findings show anastrozole to be an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with early breast cancer. For the first time a choice now exists for adjuvant endocrine treatment for postmenopausal women with hormone responsive tumours. Longer follow-up will further define the benefit/risk of anastrozole adjuvant therapy.     

A randomized trial of cognitive rehabilitation in cancer survivors

Aims

The second most frequently reported post-treatment symptom in cancer survivors are concerns about impaired cognition. Despite numerous studies demonstrating significant impairments in a portion of survivors, information on effective treatments remains an emerging area of research. This study examined the effectiveness of a group-based cognitive rehabilitation intervention in cancer survivors.

Main methods

This study was a randomized, controlled study of a 7-week cognitive rehabilitation intervention delivered in group format. Participants were evaluated with subjective symptom questionnaires and objective neurocognitive tests prior to and following treatment.

Key findings

Twenty-eight participants (mean age 58 years) with a median of 3 years (± 6 years) post-primary/adjuvant treatment and various cancer sites (breast, bladder, prostate, colon, uterine) completed the study. Compared to baseline, the treatment group demonstrated improvements in symptoms of perceived cognitive impairments (p < .01), cognitive abilities (p < .01) and overall quality of life with regard to cognitive symptoms (p < .01) as measured by the FACT-Cog. The treatment group also improved on objective measures of attention (p < .05) and a trend toward improvement on verbal memory. Significant improvement was not observed on all cognitive tests.

Significance

A group based cognitive rehabilitation intervention in cancer survivors was effective for improving attention abilities and overall quality of life related to cognition. Results suggest that group based cognitive rehabilitation may be an effective intervention for treating cognitive dysfunction in cancer patients and should be further studied in a larger trial with an active control condition.     

Spatial working memory in rats: no differences between the sexes

In a number of mammalian species, males appear to have superior spatial abilities to females. The favoured explanations for this cognitive difference are hormonal, with higher testosterone levels in males than females leading to better spatial performance, and evolutionary, where sexual selection has favoured males with increased spatial abilities for either better navigational skills in hunting or to enable an increased territory size. However, an alternative explanation for this sex difference focuses on the role of varying levels of oestrogen in females in spatial cognition (the 'fertility and parental care' hypothesis). One possibility is that varying oestrogen levels result in variation in spatial learning and memory so that, when tested across the oestrous cycle, females perform as well as males on days of low oestrogen but more poorly on days of high oestrogen. If day in the oestrous cycle is not taken into account then, across an experiment, any sex differences found would always produce male superiority. We used a spatial working memory task in a Morris water maze to test the spatial learning and memory abilities of male and female rats. The rats were tested across a number of consecutive days during which the females went through four oestrous cycles. We found no overall sex differences in latencies to reach a submerged platform in a Morris water maze but, on the day of oestrus (low oestrogen), females took an extra swim to learn the platform's location (a 100% increase over the other days in the cycle). Female swim speed also varied across the oestrous cycle but females were no less active on the day of oestrus. These results oppose the predictions of the fertility and parental care hypothesis.     

Correlation of cognitive functions with some aspects of illness, treatment and social functioning in recurrently hospitalized schizophrenic patients

Cognitive deficits are found to be contributors to poorer psychosocial functioning, rehabilitation outcome and lack of treatment success in schizophrenia. Aim of the study was to examine correlation of cognitive functions with some aspects of illness, treatment and social functioning in a group of recurrently hospitalized schizophrenic patients (N=60). Deficient results on psychomotor processing speed, verbal fluency and verbal learning correlated with the longer duration of illness, higher number of hospitalizations and shorter duration of regular antipsychotic treatment. Deficient results on verbal fluency correlated with the younger age of onset, poor functional autonomy and organizational skills, whereas deficient results on psychomotor processing and verbal learning correlated with poor organizational skills alone. Score on verbal fluency was predictive of social skills impairment, whereas score on psychomotor processing was predictive of functional autonomy and organizational skills impairment. Functioning of different cognitive domains could be predictive of functioning in different social domains. Interplay of specific cognitive deficit and social functioning could be responsible for recurrent hospitalizations and unfavorable treatment choices.     

A Double-Blind,Placebo-Controlled Trial of Donepezil for the Treatment of Menopause-Related Cognitive Loss

Background: Perimenopausal and menopausal women are more likely to complain of memory loss than are premenopausal women, although the association between menopause and cognitive loss remains controversial. Recently published studies on the risks of hormone therapy have left many women and their physicians seeking effective nonhormonal treatments for menopausal symptoms, including cognitive loss.Objective: This study investigated the efficacy of the cholinesterase agent donepezil in the treatment of menopause-related cognitive loss.Methods: Community-dwelling women in natural menopause were recruited for a randomized, double-blind, placebo-controlled study of donepezil. To qualify for enrollment, the Brief Cognitive Rating Scale was used to determine cognitive symptoms, and women with depression were excluded. Subjects were randomized to receive either donepezil, commencing at 5 mg/d, or placebo. At week 6 of randomization, the dosage of donepezil was increased to 10 mg/d. Treatment continued throughout the 26-week study. The primary outcome measure was the overall change in neurocognitive test results over time. Outcome variables of test scores were analyzed before and after receipt of donepezil or placebo.Results: A total of 28 women aged 46 to 60 years were enrolled. Fourteen women were randomized to receive active drug, 14 to placebo. Two women dropped out of the placebo group. There were no statistically significant differences between treatment groups in post-/pre-dose mean score ratios. No interactions were statistically significant. The P values for tests of equal variances did not reveal a difference in the means. Subjective measures did show some trends toward improvement in memory and cognition.Conclusion: Donepezil was no more effective than placebo in treating the symptoms of menopause- related memory and cognitive loss.     

Biological and clinical aspects of prolactin receptors (PRL-R) in human breast cancer

PRL has a definite activity in the induction and promotion of mouse and in the growth of rat mammary tumors. We and others have found that human PRL or growth hormone (GH) had a growth promoting effect on human mammary cancer cells. It has been shown that prolactin receptors (PRL-R) which are specific for all lactogenic hormones (hPRL, hGH, hPL) are present on mammary cancer cells in long-term tissue culture and also in tumor biopsies. We found that 43% of the tumors had free PRL-R (FPRL-R) and that 72% had total PRL-R (TPRL-R) which have been desaturated in vitro. A significant correlation (Spearman test) was found between PRL-R (especially TPRL-R) on the one hand, estradiol (P<0.001) and progesterone receptors (P<0.01) on the other. The demonstration of PRL-induced proteins (PIP) might be a better sign of PRL sensitivity than the existence or PRL-R; PIP have been found by Northern blot analysis in 47% of 70 breast cancers. Overall survival (OS) and relapse-free survival (RFS) analysis with a median duration of follow-up of 5.3 yr showed that TPRL-R had a significant prognostic value only in node positive patients (χ²=5.61, P=0.02). Neither FPRL-R or TPRL-R were a significant prognostic factor when studied by Cox analysis. This confirms our previous results. Since at least some human mammary cancers appear to be PRL-dependent we carried out a multicenter randomized trial comparing as the first hormonal treatment tamoxifen (TAM) (30 mg/day)+bromocriptin (B) (5 mg/day) vs TAM + placebo. 171 patients entered this trial. No difference was observed between the two groups in response rates, duration of response or survival.

Recent studies are thus in favor of a role of lactogenic hormones during the course of breast cancer. However no improvement in therapy has been observed yet. The combination of drugs to achieve a total anti-lactogenic treatment, the use of anti-PRL-R antibodies are interesting areas of research; the recent cloning of PRL-R and GH receptors may open new clinical perspectives.     

Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant).

In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2–T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P = 0.022).

In both trials, both treatments were well tolerated with no significant differences in side effects.

These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments.     

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the postmenopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan.