The purpose of this study was to assess the impact of testosterone therapy on mood and cognitive symptoms in perimenopausal and postmenopausal women.

A retrospective cohort study undertaken in a UK specialist menopause clinic. 510 women using hormone replacement therapy (HRT) with persistent low libido, cognitive and negative mood symptoms were treated with testosterone cream or gel for 4 months. A modified version of the Greene Climacteric Scale was used to measure self-reported symptom frequency and severity at baseline and 4 months after initiating treatment.

All nine cognitive and mood symptoms significantly improved across the study period. Mood improved more than cognition (47% of women reported an improvement in mood vs. 39% reported an improvement in cognition; 34% vs. 22% decrease in mean symptom scores, respectively). Regarding libido, 52% of women reported an improvement; mean symptom score decreased by 33%.

Transdermal testosterone therapy for 4 months was associated with significant improvements in mood and cognition. Further research including randomised clinical trials are needed to establish the long-term efficacy and safety of testosterone for the treatment of menopausal cognitive and psychological symptoms.

This review discusses mental health changes commonly experienced by individuals during the menopause transition (MT). The pathophysiology of the MT, the chronology and type of mental health symptoms arising from this pathophysiology, and evidence-based options for treating midlife patients are discussed. This review concludes with treatment options to enable clinicians to more effectively counsel, recognize and treat symptoms during the MT.

The MT begins earlier than previously understood with mood and cognitive issues as common initial mental health symptoms significantly impacting quality of life. These symptoms are due to profound changes in the brain's structure, connectivity, energy metabolism, and inflammation linked to perimenopausal hormone shifts. Hormone therapy, psychiatric medication, psychotherapy, and lifestyle adjustments all play a role in the management of mental health symptoms arising during the MT. Lack of both obstetrician and gynecologist and mental health clinician awareness can leave patients undertreated and vulnerable to nonevidence-based approaches.

Patients in the MT are at increased risk for mental health issues, both preexisting and new onset. The OB/GYN clinician plays a key role in recognizing and addressing these conditions to improve health outcomes in midlife women.

The differentiation between association and causation is a significant challenge in medical research, often further complicated by cognitive biases that erroneously interpret coincidental observational data as indicative of causality. Such misinterpretations can lead to misguided clinical guidelines and healthcare practice, potentially endangering patient safety and leading to inefficient use of resources.

We conducted an extensive search of PubMed, Cochrane, and Embase databases up to March 2024, identifying circumstances where associations from observational studies were incorrectly deemed causal. These instances led to changes in clinical practice, embodying what we have termed the 'observational interpretation fallacy'.

Our search identified 16 notable cases where observational study-derived associations, initially thought to influence clinical practices and guidelines positively, were later contradicted by findings from randomised controlled trials or further studies, necessitating significant revisions in clinical practice.

In many cases, misinterpretation of observational finding negatively affecting patient care and public health policies. Addressing and rectifying the observational interpretation fallacy is crucial for the progression of medical research and the maintenance of safe and effective clinical practice. It is imperative for health policymakers, clinicians, and the lay public to critically assess research outcomes and make health-related decisions based on a foundation of evidence-based medicine. This approach ensures the alignment of medical practices with the most current and robust scientific evidence, safeguarding patient welfare and optimising resource allocation.

Women with BRCA1/2 pathogenic variants considering risk-reducing bilateral oophorectomy (RRSO) may be concerned about potential effects of surgical menopause on cognition. Whether RRSO affects cognition and whether hormone therapy (HT) modifies this effect remains uncertain. This study aimed to prospectively measure the effect of premenopausal RRSO on cognition and the modifying effects of HT up to 24 months.

The design was a prospective, multisite (4 sites in Australia), 24-month observational study. Participants were premenopausal BRCA1/2 carriers (n = 83) planning RRSO referred from gynecology-oncology and familial cancer centers and a premenopausal comparison group (n = 98) not planning oophorectomy or pregnancy who self-referred. Baseline data were collected within 8 weeks of eligibility screening, and RRSO was scheduled between baseline and 3 months. Of 687 screened, 181 were analysed. Cognitive performance (verbal learning and memory, psychomotor speed, fluency) was assessed at baseline, 3, 12 and 24 months with the a priori outcomes of verbal learning and memory.

After RRSO, 65 % initiated HT. In multivariable models of group differences in cognitive performance over time, RRSO and comparison groups showed similar performance improvements except for verbal learning. The RRSO group showed a small, statistically significant lower improvement in verbal learning vs comparisons, after adjustment for HT and other factors (p = 0.03). After RRSO, verbal learning was higher in HT users vs non-users (p = 0.04).

Over 24 months RRSO minimally impacted cognition except for a small adverse effect on verbal learning, partly offset by HT.

Australian and New Zealand Clinical Trials Registry (anzctr.org.au); Identifier #: ACTRN12615000082505; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363554&isReview=true.

Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that atypical neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions, which include (1) luteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; (2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and (3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders.

Ovarian removal prior to spontaneous/natural menopause (SM) is associated with increased risk of late life dementias including Alzheimer's disease. This increased risk may be related to the sudden and early loss of endogenous estradiol. Women with breast cancer gene mutations (BRCAm) are counseled to undergo oophorectomy prior to SM to significantly reduce their risk of developing breast, ovarian, and cervical cancers. There is limited evidence of the neurological effects of ovarian removal prior to the age of SM showing women without the BRCAm had cortical thinning in medial temporal lobe structures. A second study in women with BRCAm and bilateral salpingo-oophorectomy (BSO) noted changes in cognition.

The present, cross-sectional study examined whole-brain differences in gray matter (GM) volume using high-resolution, quantitative magnetic resonance imaging in women with BRCAm and intact ovaries (BRCA-preBSO [study cohort with BRCA mutation prior to oophorectomy]; n = 9) and after surgery with (BSO + estradiol-based therapy [ERT]; n = 10) and without (BSO; n = 10) postsurgical estradiol hormone therapy compared with age-matched women (age-matched controls; n = 10) with their ovaries.

The BRCA-preBSO and BSO groups showed significantly lower GM volume in the left medial temporal and frontal lobe structures. BSO + ERT exhibited few areas of lower GM volume compared with age-matched controls. Novel to this study, we also observed that all three BRCAm groups exhibited significantly higher GM volume compared with age-matched controls, suggesting continued plasticity.

The present study provides evidence, through lower GM volume, to support both the possibility that the BRCAm, alone, and early life BSO may play a role in increasing the risk for late-life dementia. At least for BRCAm with BSO, postsurgical ERT seems to ameliorate GM losses.

This study aimed to understand the meaning of the phrase "not feeling like myself" (NFLM) when used by those on the path to menopause by exploring the relationship of symptoms reported to ratings of NFLM.

Participants responded to the item "Many women report just not feeling like themselves during this phase of life. How often was this true for you over the past 3 months?" choosing from "none of the time" to "all of the time." They rated bother associated with 61 symptoms and provided demographic information. Individual symptoms and the symptom bother scale scores were correlated with NFLM. Symptom scale scores were then entered in a two-stage multiple regression model to identify symptoms associated significantly with NFLM.

Sixty-three percent (63.3%) of participants reported NFLM 50% of the time or more over the previous 3 months. Individual symptom ratings correlated with NFLM ( r > 0.300) included the following: fatigue ( r = 0.491); feeling overwhelmed/less able to cope ( r = 0.463); low feelings ( r = 0.440); anxiety, more nervousness ( r = 0.398); being irritable ( r = 0.380); harder time concentrating ( r = 0.378); difficulty making decisions ( r = 0.357); feeling like "I can't calm down on the inside" ( r = 0.333); being more forgetful ( r = 0.332); tearfulness/crying ( r = 0.306); and worrying more ( r = 0.302). A two-stage regression analysis revealed less education completed and greater overall stress ratings as significant predictors in stage 1. In stage 2, five symptom groups met the P < 0.001 criterion: anxiety/vigilance, fatigue/pain, brain fog, sexual symptoms, and volatile mood symptoms.

NFLM was associated with anxiety/vigilance, fatigue/pain, brain fog, sexual symptoms, and volatile mood symptoms. Recognizing symptoms associated with NFLM may allow for more accurate expectations and improve perimenopause care.

Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial.

We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants.

Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT.

These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause.

A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES-D).

We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2).

In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2).

The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.Reprinted from Maturitas 2023; 170:64-73, with permission from Elsevier. Copyright © 2023.

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer's disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17β-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17β-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17β-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and neural biomarkers are associated with cognitive problems and which interventions demonstrate efficacy at improving cognitive performance.

Cognitive problems are common during perimenopause and have a significant impact on a substantial proportion of women. Evidence continues to indicate that verbal learning and verbal memory are the cognitive functions that are most negatively affected during perimenopause, and new research suggests that perimenopause may also be associated with deficits in processing speed, attention, and working memory. Recent research suggests that the cognitive profiles of women transitioning through perimenopause are heterogenous - with some showing strengths and others demonstrating weaknesses in particular cognitive domains. Depression, sleep problems, and vasomotor symptoms in perimenopause may be associated with cognitive difficulties. Recent neuroimaging studies are identifying changes in activity patterns within brain regions that correlate with cognitive performance in perimenopause, but future causal studies are needed to understand the neural mechanisms of cognitive problems during this time. Although clinical treatment studies for cognitive concerns have historically focused on postmenopause, some small trials in perimenopausal samples have been conducted recently but are frequently underpowered. Current guidelines from the North American Menopause Society do not support the use of hormone therapy at any age for cognitive problems. Animal research demonstrates that estradiol and levonorgestrel combined may alleviate working memory problems. Much progress has been made in understanding how perimenopause impacts cognition, and more research is needed to better identify who is at highest risk and how to meaningfully prevent and alleviate cognitive problems during this reproductive stage. Larger-scale randomized intervention trials specifically during perimenopause are urgently needed to address cognitive concerns in this population of women. More consistent reproductive staging, inclusion of covariates, and analyses examining perimenopause specifically would improve study quality and the ability to draw clear conclusions from this research.

More women have Alzheimer disease (AD) than men, but the reasons for this phenomenon are still unknown. Including women in clinical research and studying their biology is key to understand not just their increased risk but also their resilience against the disease. In this sense, women are more affected by AD than men, but their reserve or resilience mechanisms might delay symptom onset. The aim of this review was to explore what is known about mechanisms underlying women's risk and resilience in AD and identify emerging themes in this area that merit further research. We conducted a review of studies analyzing molecular mechanisms that may induce neuroplasticity in women, as well as cognitive and brain reserve. We also analyzed how the loss of steroid hormones in aging may be linked to AD. We included empirical studies with human and animal models, literature reviews as well as meta-analyses. Our search identified the importance of 17-b-estradiol (E2) as a mechanism driving cognitive and brain reserve in women. More broadly, our analysis revealed the following emerging perspectives: (1) the importance of steroid hormones and their effects on both neurons and glia for the study of risk and resilience in AD, (2) E2's crucial role in women's brain reserve, (3) women's verbal memory advantage as a cognitive reserve factor, and (4) E2's potential role in linguistic experiences such as multilingualism and hearing loss. Future directions for research include analyzing the reserve mechanisms of steroid hormones on neuronal and glial plasticity, as well as identifying the links between steroid hormone loss in aging and risk for AD.

Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration. However, the mechanisms underlying memory decline and other cognitive dysfunctions following OVX are unclear. Given that iron accumulates during ageing and after OVX, we hypothesized that excess iron accumulation in the hippocampus would cause ferroptosis-induced increased neuronal degeneration and death associated with memory decline. In the current study, female rats that underwent OVX showed decreased dihydroorotate dehydrogenase (DHODH) expression and reduced performance in the Morris water maze (MWM). We used primary cultured hippocampal cells to explore the ferroptosis resistance-inducing effect of 17β-oestradiol (E₂). The data supported a vital role of DHODH in neuronal ferroptosis. Specifically, E₂ alleviated ferroptosis induced by erastin and ferric ammonium citrate (FAC), which can be blocked by brequinar (BQR). Further in vitro studies showed that E₂ reduced lipid peroxidation levels and improved the behavioural performance of OVX rats. Our research interprets OVX-related neurodegeneration with respect to ferroptosis, and both our in vivo and in vitro data show that E₂ supplementation exerts beneficial antiferroptotic effects by upregulating DHODH. Our data demonstrate the utility of E₂ supplementation after OVX and provide a potential target, DHODH, for which hormone therapy has not been available.

The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause.

A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CESD).

We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2).

In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2).

The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.

Endocrine, nervous, and immune systems work coordinately to maintain the global homeostasis of the organism. They show sex differences in their functions that, in turn, contribute to sex differences beyond reproductive function. Females display a better control of the energetic metabolism and improved neuroprotection and have more antioxidant defenses and a better inflammatory status than males, which is associated with a more robust immune response than that of males. These differences are present from the early stages of life, being more relevant in adulthood and influencing the aging trajectory in each sex and may contribute to the different life lifespan between sexes.

Menopause is a natural stage that occurs when women stop menstruating, during which many women experience physical and psychological symptoms that can affect their quality of life and ability to work. Dietary modifications and food supplements may be explored by some women as alternatives to hormone replacement therapy, although existing reviews and expert position statements have given this limited consideration. This narrative review summarises the current evidence for dietary patterns, and botanical and food supplements, in the management of common menopausal symptoms, including vasomotor symptoms (VMS; hot flushes; night sweats), changes in bodyweight and composition, psychological symptoms (depression; anxiety; cognitive changes), sleep disturbances, joint pain, skin changes and urogenital symptoms. Soy isoflavones may reduce the frequency and/or severity of VMS, although results are inconsistent, and it is unclear whether dietary and supplemental sources have comparable effects. Adopting a healthier dietary pattern may support a healthy bodyweight and benefit VMS. However, evidence suggesting dietary patterns may benefit depression, anxiety, and cognition remains largely observational. While some botanicals, such as black cohosh and St John's Wort, have been reported in some studies to alleviate symptoms (such as VMS and depression), these are not currently recommended due to uncertainty about the appropriate dose and preparation, and potential safety concerns. Evidence for other symptoms is currently too limited to draw conclusions. While further trials at different menopausal stages are needed, adopting a healthier dietary pattern in accordance with dietary guidelines is likely to help support women's health before, during and after the menopausal transition.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for more than half of all dementia cases in the elderly. Interestingly, the clinical manifestations of AD disproportionately affect women, comprising two thirds of all AD cases. Although the underlying mechanisms for these sex differences are not fully elucidated, evidence suggests a link between menopause and a higher risk of developing AD, highlighting the critical role of decreased estrogen levels in AD pathogenesis. The focus of this review is to evaluate clinical and observational studies in women, which have investigated the impact of estrogens on cognition or attempted to answer the prevailing question regarding the use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS, and PubMed (keywords "memory", "dementia," "cognition," "Alzheimer's disease", "estrogen", "estradiol", "hormone therapy" and "hormone replacement therapy" and by searching reference sections from identified studies and review articles). This review presents the relevant literature available on the topic and discusses the mechanisms, effects, and hypotheses that contribute to the conflicting findings of HRT in the prevention and treatment of age-related cognitive deficits and AD. The literature suggests that estrogens have a clear role in modulating dementia risk, with reliable evidence showing that HRT can have both a beneficial and a deleterious effect. Importantly, recommendation for the use of HRT should consider the age of initiation and baseline characteristics, such as genotype and cardiovascular health, as well as the dosage, formulation, and duration of treatment until the risk factors that modulate the effects of HRT can be more thoroughly investigated or progress in the development of alternative treatments can be made.

Midlife women commonly experience changes in their cognitive function as they transition through menopause and express concern about whether these changes represent the initial stages of a more serious cognitive disorder. Health-care practitioners play an important role in counseling women on cognitive changes at midlife and normalizing women's experience. The aim of this commissioned International Menopause Society White Paper on cognition is to provide practitioners with an overview of data informing the clinical care of menopausal women and a framework for clinical counseling and decision-making. Among the topics presented are the specific cognitive changes occurring in menopause, the duration of such changes and their severity. The role of estrogen and menopause symptoms is reviewed. We present talking points for clinical counseling on the effects of hormone therapy on cognition and dementia risk in women, including discussion of absolute risk. Lastly, a brief review of modifiable risk factors for age-related cognitive decline and dementia is presented, with guidance for counseling patients on optimizing their brain health at midlife and beyond.

After advanced age, female sex is the major risk factor for late-onset Alzheimer's disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10-20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.

Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.

Factors that influence the risk of neurocognitive decline and Alzheimer's disease (AD) may provide insight into therapies for both disease treatment and prevention. While age is the most striking risk factor for AD, it is notable that the prevalence of AD is higher in women, representing two-thirds of cases. To explore potential underlying biological underpinnings of this observation, the intent of this article is to explore the interplay between cognitive aging and sex hormones, the cholinergic system, and novel hypotheses related to the essential nutrient, choline. Mechanistic evidence points toward estrogen's neuroprotective effects being strongly dependent on its interactions with the cholinergic system, a modulator of attentional functioning, learning, and memory. Estrogen has been shown to attenuate anticholinergic-induced impairments in verbal memory and normalize patterns of frontal and occipital cortex activation, resulting in a more "young adult" phenotype. However, similar to estrogen replacement's effect in cardiovascular diseases, its putative protective effects may be restricted to early postmenopausal women only, supportive of the "critical window hypothesis." Estrogen's impact on the cholinergic system may act both locally in the brain but also through peripheral tissues. Estrogen is critical for inducing endogenous choline synthesis via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway of phosphatidylcholine (PC) synthesis. PEMT is dramatically induced in response to estrogen, producing not only a PC molecule and source of choline for the brain but also a key source of the long-chain omega-3 fatty acid, DHA. Herein, we highlight novel hypotheses related to hormone replacement therapy and nutrient metabolism aimed at directing future preclinical and clinical investigation.

Alzheimer's disease (AD) includes a long asymptomatic stage, which precedes the formal diagnosis of dementia. AD biomarker models provide a framework for precision medicine approaches during this stage. However, such approaches have ignored the possible influence of sex on cognition and brain health, despite female sex noted as a major risk factor. Since AD-related changes may emerge in midlife, intervention efforts are being redirected around this period. Midlife coincides with several endocrinological changes, such as the menopausal transition experienced by women. In this narrative review, we discuss evidence for sex-differences in AD neuropathological burden and outline key endocrinological mechanisms for both sexes, focussing on hormonal events throughout the lifespan that may influence female susceptibility to AD neuropathology and dementia onset. We further consider common non-modifiable (genetic) and modifiable (lifestyle and health) risk factors, highlighting possible sex-dependent differential effects for the AD disease course. Finally, we evaluate the studies selected for this review demonstrating sex-differences in cognitive, pathological and health factors, summarising the state of sex differences in AD risk factors. We further provide recommendations for targeted research on female-specific risk factors, to inform personalised strategies for AD-prevention and the promotion of female brain health.

Women experience different degrees of subjective cognitive changes during pregnancy. The exact mechanism underlying these changes is unknown, although endocrine alterations and genetics may be contributing factors. We investigated whether multiple pregnancy-related hormones were associated with working memory function assessed with the Digit Span Test (DST) in late pregnancy. Moreover, we examined whether the catechol-O-methyltransferase (COMT) genotype, previously related to working memory, was an effect modifier in this association. In this population-based panel study, we recorded psychiatric history, medication use, socio-demographic characteristics, and psychological well-being, gathered blood and saliva samples, and administered the DST at gestational weeks 35-39 (N = 216). We conducted multivariate linear regressions with DST as outcome, with different hormones and COMT genotype, adjusting for covariates including maternal age, BMI, education, depressive symptoms, and parity. We repeated these analyses excluding women with elevated depressive symptoms. Higher DST total scores were associated with increased free estradiol concentrations (B = 0.01, p = 0.03; B = 0.01, p = 0.02) in all participants and in participants without depressive symptoms, respectively, whereas DST forward was positively associated with free estradiol only in women without depressive symptoms (B = 0.01, p = 0.04). Lower total testosterone concentrations (B = -0.03, p = 0.01) enhanced DST backward performance in non-depressed women. Maternal higher education was significantly associated with the DST subscales in all participants. No significant differences emerged when considering the COMT genotype. Our results suggest differential associations of free estradiol and total testosterone levels with working memory function in late pregnancy.

There has been a proliferation of studies demonstrating important sex differences in cognitive aging and dementia, and with this an increased interest in the role of menopause and sex steroid hormones in women's brain health. Foundational longitudinal studies of cognitive changes from the premenopause to perimenopause stage have shown reliable declines in verbal memory, with variable findings in processing speed, attention/working memory and verbal fluency. Continued research is needed to advance understanding of the range of cognitive domains affected, the duration of cognitive changes, the generalizability of these changes across cultures, the factors that account for such changes and the factors that can improve cognition at this time. In this article, we briefly review and draw on findings from large longitudinal studies of cognitive changes across the menopause transition to inform the design of future studies on this topic. We focus on key issues such as objective versus subjective cognitive measures; cognitive domains and tests; staging menopause; study design; mediators of cognitive effects (including hormones and menopause symptoms); and consideration of key covariates. We suggest that a more uniform and evidence-based approach to the investigation of these issues can advance the quality of the science in menopause and cognition.

The objective of this study was to evaluate the impact of various surgical, hormonal, and lifestyle factors on memory and attention in women with a BRCA1 or BRCA2 mutation.

BRCA mutation carriers enrolled in a longitudinal study were invited to complete an online brain health assessment tool designed to screen for cognitive deficits. Four measures of memory and executive attention were assessed individually, and an overall score was compiled adjusting for age. Exposures, including preventive surgery, hormone use, and lifestyle factors, were captured by questionnaire. Performance on each of the 5 subtasks was analyzed according to various exposures. Analysis of covariance was used to compare overall scores.

In total, 880 women completed the online cognitive assessment. The average age of the participants was 54 years (range, 23-86 years). The mean overall test score was 54.4 (range, 0-93). The individual subtask scores declined with age at test completion (P < .0001) and increased with level of education (P ≤ .01). Women who underwent a preventive oophorectomy had a significantly higher overall score compared with women who did not undergo this surgery (55.5 vs 50.5; P = .01). Reconstructive breast surgery was also associated with a higher overall score (56.5 vs 52.3; P = .005). Chemotherapy and hormone-replacement therapy were not predictive of the overall score.

These findings are reassuring to high-risk women who undergo early surgical menopause for their cancer predisposition. Further studies are needed to evaluate cognitive function over time when memory deficits become more prevalent.

Premenopausal breast cancer is usually estrogen receptor positive, and hence, prolonged ovarian suppression by medical or surgical means to prevent recurrence has become standard of management to improve disease-free survival. Ten-year adjuvant tamoxifen therapy is associated with 3.5% fewer recurrences compared to five years. The SOFT trial demonstrated small but statistically significant incremental improvements in long-term disease-free survival by the addition of gonadotropin-releasing hormone analog treatment (triptorelin) to an aromatase inhibitor (exemestane). Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality. This paper explores multi-system consequences of prolonged hypoestrogenism in premenopausal women derived from studies of women with and without breast cancer. Pretreatment counseling in estrogen receptor positive breast cancer should emphasize the benefit of prolonged estrogen suppression on breast cancer recurrence and established risks of lifelong hypoestrogenism on quality of life and all-cause mortality. Future genomic research may help identify the best candidates for extended ovarian suppression to avoid treating many women when only a minority benefit.

The putative association between hormones and cognitive performance is controversial. While there is evidence that estradiol plays a neuroprotective role, hormone treatment has not been shown to improve cognitive performance. Current research is flawed by the evaluation of combined hormonal effects throughout the menstrual cycle or in the menopausal transition. The stimulation phase of a fertility treatment offers a unique model to study the effect of estradiol on cognitive function. This quasi-experimental observational study is based on data from 44 women receiving IVF in Zurich, Switzerland. We assessed visuospatial working memory, attention, cognitive bias, and hormone levels at the beginning and at the end of the stimulation phase of ovarian superstimulation as part of a fertility treatment. In addition to inter-individual differences, we examined intra-individual change over time (within-subject effects). The substantial increases in estradiol levels resulting from fertility treatment did not relate to any considerable change in cognitive functioning. As the tests applied represent a broad variety of cognitive functions on different levels of complexity and with various brain regions involved, we can conclude that estradiol does not show a significant short-term effect on cognitive function.

Perimenopause is associated with declines in attention, working memory and verbal memory; however, there are significant individual differences. Further, the contributions of hormones and menopausal symptoms to domain-specific cognitive functions remain unknown. This longitudinal study aimed to determine whether there were distinct cognitive profiles in perimenopause and to identify factors associated with each profile.

In a sample of 85 women evaluated over 400 bi-annual visits, we administered a comprehensive neuropsychological battery, assessed menopausal symptoms and measured 17β-estradiol and follicle stimulating hormone. Multilevel latent profile analysis was used to identify cognitive profiles. Regressions were conducted to determine differences in hormones and symptoms by profile after adjusting for Stages of Reproductive Aging Workshop + 10 (STRAW + 10) stage and demographic factors.

Perimenopausal cognitive profiles consisted of cognitively normal (Profile 1; n = 162), weaknesses in verbal learning and memory (Profile 2; n = 94), strengths in verbal learning and memory (Profile 3; n = 98) and strengths in attention and executive function (Profile 4; n = 61). Profile 2 was differentiated by less hormonal variability and more sleep disturbance than Profile 1 (p < 0.05).

There is significant heterogeneity in cognition during perimenopause. While most women do not develop impairments, a significant minority experience weaknesses in verbal learning and memory. Profile analysis may identify at-risk populations and inform interventions.

Transdermal testosterone therapy, dosed within premenopausal physiologic testosterone ranges, used alone or with menopausal hormone therapy for postmenopausal hypoactive sexual desire disorder, has shown short-term efficacy, with few androgenic side effects. After natural or surgical menopause, meaningful improvements include an additional satisfying sexual episode per month; improvement in desire, arousal, orgasm, pleasure, and responsiveness; and a reduction in distress. Long-term data on cardiovascular, cancer, and cognitive safety are lacking. No approved testosterone preparation is available for women. Compounded testosterone creams or reduced dosing of male-approved therapies represent off-label use. Injections or pellets cause supraphysiological testosterone levels and are not recommended.

To assess longitudinal changes in cognitive performance across menopause stages in a sample comprised primarily of low-income women of color, including women with HIV (WWH).

A total of 443 women (291 WWH; 69% African American; 18% Hispanic; median age = 42 y) from the Women's Interagency HIV Study completed tests of verbal learning and memory, attention/working memory, processing speed, verbal fluency, motor skills, and executive function first at an index premenopausal visit and thereafter once every 2 years for up to six visits (mean follow-up = 5.7 y). General linear-mixed effects regression models were run to estimate associations between menopause stages and cognition, in the overall sample and in WWH. We examined both continuous scores and categorical scores of cognitive impairment (yes/no >1 standard deviation below the mean).

Adjusting for age and relevant covariates, the overall sample and WWH showed longitudinal declines in continuous measures of learning, memory, and attention/working memory domains from the premenopause to the early perimenopause and from the premenopause to the postmenopause, Ps < 0.05 to < 0.001. Effects on those same domains were also evident in categorical scores of cognitive impairment, with the increased odds of impairment ranging from 41% to 215%, Ps < 0.05 to < 0.001. The increase in predicted probability of impairment by menopausal stage (% affected) ranged from 4% to 13%.

Menopause stage was a key determinant of cognition in a sample of low-income women of color, including WWH. Many of these changes reached a clinically significant level of cognitive impairment.

Vasomotor symptoms (VMS) are associated with decreased memory performance and alterations in brain function. We conducted a preliminary examination of VMS and patterns of brain activity during a verbal memory task to provide insights into the VMS-related brain mechanisms that can contribute to memory problems in midlife women.

Fourteen postmenopausal women (mean age 53.5, 64% African-American) with moderate-to-severe VMS (>35/wk) and not taking hormone therapy completed functional magnetic resonance imaging (fMRI) assessments during word encoding and recognition, 24-hour physiologic VMS monitoring, symptom questionnaires, and two verbal memory tests.

In regression analyses, a higher number of physiologic VMS, but not reported VMS, was associated with worse verbal memory on immediate and delayed logical memory (r = 0.53 and r = 0.72, P < 0.05). On fMRI assessments, a higher number of physiologic VMS, but not subjective VMS, was associated with greater activation in the left orbitofrontal cortex, left medial and superior frontal gyrus, right superior frontal gyrus, and right parahippocampal gyrus during the encoding task (P < 0.005). During the recognition task, physiologic VMS were associated with greater activation in the left medial and superior frontal gyrus, left parahippocampal gyrus and hippocampus, right medial and superior frontal gyrus, right parahippocampal gyrus and hippocampus (P < 0.005), and with decreased activation in the ventral medial prefrontal cortex (P < 0.005). Those associations were independent of symptoms and hormone levels.

Preliminary data suggest that VMS may contribute to memory performance through effects on the hippocampus and prefrontal cortex. Larger studies are warranted to determine the robustness of these initial observations. : Video Summary:http://links.lww.com/MENO/A508.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective strategy to prevent pelvic serous carcinoma for women at high risk of developing ovarian cancer; however, it results in premature menopause. Data is lacking to adequately counsel these women about potential effects of premature menopause on cognition and quality of life.

A prospective study in premenopausal women at high risk of ovarian cancer to determine changes in cognition over time after RRSO and the impact of hormone therapy (HT) on cognition. Participants were surveyed before and after surgery using the Functional Assessment of Cancer Therapy-Cognitive questionnaire and questions regarding domains of wellbeing at 6, 12 and 18 months. Data was tested for changes across time using mixed model regression and logistic regression.

Fifty-seven women were included. Sixty-three percent of participants used HT. At 6 months postoperatively, perceived cognitive impairment declined by 5.5 points overall (4.4 in non-HT users and 6 in HT users), P = 0.003. The other domains of cognition assessed did not change significantly over time and the use of HT did not impact scores. Sleep disruption was common in this cohort and was not mitigated by HT. Self-reported depression improved after RRSO (P = 0.004).

Women at high risk of ovarian cancer who choose RRSO may experience declines in cognition within the first 6 months of surgical menopause. HT may cause small declines in perceived cognitive impairment at 6 months after RRSO. Women can expect more sleep disruption after menopause, which is not mitigated by HT.

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally connecting genetic risk factors for Alzheimer's disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer's disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca²⁺ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.

The role of androgens in shaping "masculine" traits in males is a core focus in behavioral endocrinology, but relatively little is known about an androgenic role in female aggression and social dominance. In mammalian models of female dominance, including the ring-tailed lemur (Lemur catta), links to androgens in adulthood are variable. We studied the development of ring-tailed lemurs to address the behavioral basis and ontogenetic mechanisms of female dominance. We measured behavior and serum androgen concentrations in 24 lemurs (8 males, 16 females) from infancy to early adulthood, and assessed their 'prenatal' androgen milieu using serum samples obtained from their mothers during gestation. Because logistical constraints limited the frequency of infant blood sampling, we accounted for asynchrony between behavioral and postnatal hormone measurements via imputation procedures. Imputation was unnecessary for prenatal hormone measurements. The typical sex difference in androgen concentrations in young lemurs was consistent with adult conspecifics and most other mammals; however, we found no significant sex differences in rough-and-tumble play. Female (but not male) aggression increased beginning at approximately 15 months, coincident with female puberty. In our analyses relating sexually differentiated behavior to androgens, we found no relationship with activational hormones, but several significant relationships with organizational hormones. Notably, associations of prenatal androstenedione and testosterone with behavior were differentiated, both by offspring sex and by type of behavior within offspring sexes. We discuss the importance of considering (1) missing data in behavioral endocrinology research, and (2) organizational androgens other than testosterone in studies of female dominance.

Alzheimer's disease (AD) is an age- and gender-associated brain disorder. Long noncoding RNAs (lncRNAs) have emerged as key regulators of brain development, homeostasis, and pathologies. Here, we used gene array data sets and bioinformatics analysis to identify differentially expressed age- and gender-associated lncRNAs in human AD brains. We found that the expressions of 16 age-associated and 13 gender-associated lncRNAs were dysregulated in AD brains. Notably, the expressions of age-associated lncRNAs-SNHG19 and LINC00672-were significantly correlated with Braak stage of AD, positively and negatively, respectively, whereas the expressions of gender-associated lncRNAs-RNF144A-AS1, LY86-AS1, and LINC00639-were negatively correlated with Braak stage of AD. Functional analysis suggests that the pathways involved in neurodegenerative diseases, synaptic vesicle cycle, and endocytosis were overly represented within age- and gender-associated lncRNA-correlating genes. The identification of age- and gender-associated lncRNAs and their differential expressions in the human AD brain provide potential targets for further experimental validation and mechanistic investigation, which could, in turn, pave the way for developing age- and gender-specific prevention and adjunctive therapeutic options for patients with AD.

Hormone therapy (HT) is reported to be deficient in improving learning and memory in older postmenopausal women according to recent clinical studies; however, the reason for failure is unknown. A "window of opportunity" for estrogen treatment is proposed to explain this deficiency. Here, we found that facilitation of memory extinction and long-term depression by 17β-estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrease of miR-221-5p, which promoted cannabinoid receptor 1 (CB1) ubiquitination by upregulation of Neurl1a/b in E2-treated OVXLT mice. Blood samples from postmenopausal women aged 56-65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46-55. Replenishing of miR-221-5p or treatment with a CB1 agonist rescued the impairment of fear extinction in E2-treated OVXLT mice. The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.

Stroke risk and poor stroke outcomes in postmenopausal women have usually beeen attributed to decreased levels of estrogen. However, two lines of evidence suggest that this hormone may not be solely responsible for elevated stroke risk in this population. First, the increased risk for CVD and stroke occurs much earlier than menopause at a time when estrogen levels are not yet reduced. Second, estrogen therapy has not successfully reduced stroke risk in all studies. Other sex hormones may therefore also contribute to stroke risk. Prior to menopause, levels of the gonadotrophin Follicle Stimulating Hormone (FSH) are elevated while levels of the gonadal peptide inhibin are lowered, indicating an overall decrease in ovarian reserve. Similarly, reduced estrogen levels at menopause significantly increase the ratio of androgens to estrogens. In view of the evidence that androgens may be unfavorable for CVD and stroke, this elevated ratio of testosterone to estrogen may also contribute to the postmenopause-associated stroke risk. This review synthesizes evidence from different clinical populations including natural menopause, surgical menopause, women on chemotherapy, and preclinical stroke models to dissect the role of ovarian hormones and stroke risk and outcomes.

Background/Study Context: A number of longitudinal randomized controlled trials (LRCT) have used free verbal recall tests to study the effects of post-menopausal estrogen hormone therapy (HT) on episodic memory, but none have explicitly explored contrasts between list and story recall, in spite of cognitive differences between the tasks. For example, list recall provides little support for the use of gist, while story recall emphasizes it, and there is evidence that estrogen produces gist bias. Moreover, we present a literature tabulation that also suggests a task-specific HT effect.

In an LRCT with up to eight yearly test sessions, post-menopausal women were randomly assigned either to placebo (N = 56) or to an estrogen formulation (N = 44); subgroups received either estrogen alone (hysterectomy; E-alone; N = 16) or with progestin (intact uterus; E + P; N = 28). Participants were tested on the immediate and delayed list and story recall at each session.

Linear mixed effects analyses of longitudinal trajectories showed that relative to placebo, the HT group declined significantly faster on immediate list recall and slower on immediate story recall. Separate analyses produced a sharpened version of this pattern for the E-alone subgroup but found no significant effects for the E + P subgroup. No significant effects were found in delayed testing.

The dissociation we found for immediate list and story recall is similar to the pattern of results in our literature tabulation. Fuzzy-Trace Theory posits parallel verbatim and gist traces plus a meta-cognitive review which becomes more gist-biased with age. Our results suggest that: (1) estrogen increases gist bias, hastening the normal age-related decline of list recall but slowing the decline of story recall relative to placebo; (2) decay of the verbatim trace over time generally causes a shift to gist, thereby accounting for the absence of a delayed recall difference; and (3) progestin weakens the effects of estrogen, thereby accounting for why the dissociation found in E-alone was absent in the E + P subgroup.