Ming Jun Kuck and Eef Hogervorst consider the data on the safety and potential cognitive effects in later life of midlife menopausal hormone treatment in women.

Anti-inflammatory properties of androgens were assessed in animal models, but only several clinical studies investigated the effects of androgen on multiple sclerosis (MS). Inflammatory activity in MS often attenuates with aging, and androgen modifying therapies (AMT), which mimic decreased androgen levels, are frequently used in older men. We aimed to investigate if the number of disease activity events would increase in older (≥55 years) male persons with MS (MPwMS) who are on AMT.

MPwMS with AMT initiation ≥55 years (AMT; n = 60) and without AMT history (no-AMT; n = 80) were included from a clinical-based observational study cohort. Clinical (relapses), Radiological (new lesions), and Disease (relapses and/or new lesions) activity events were evaluated before and after the age at AMT initiation in AMT and no-AMT groups.

Age at MS onset, progressive MS rate and treatment frequencies were similar between the groups. When events before and after the age at AMT initiation (mean = 65.0 ± 7.0 years) were compared, there was a drop in the percentage of individuals with Clinical (38.5 % vs. 10 %), Radiological (46.2 % vs. 40 %) and Disease (62.8 % vs. 40 %) activity events in the no-AMT group. In the AMT group, the percentage of individuals with Clinical activity events was not as dramatically decreased (33.3 % vs. 22.2 %), Radiological activity events was increased (35.2 % vs. 46.7 %), and Disease activity events was sustained (51.9 % vs. 51.1 %). The probability of Disease activity was higher in the AMT group at 3 years of AMT initiation (40 % vs. 29 %) compared to the no-AMT group matched for disease duration, but the difference was not significant (p = 0.582).

Rather than the expected decrease in disease activity with age, MPwMS receiving AMT experienced sustained or increased disease activity, particularly at >65 years. Close clinical monitoring of MPwMS starting on these medications is necessary.

Accumulating evidence suggests that the effects of menopausal hormone therapy (MHT) on risk of Alzheimer disease (AD) and all-cause dementia are influenced by timing of initiation relative to age, time-since-menopause, and the type of formulation. Randomized clinical trials (RCTs) of MHT conducted in postmenopausal women ages 65 and older indicated an increased risk of dementia. While RCTs conducted in midlife are lacking, observational research has provided evidence for associations between midlife estrogen-only therapy (ET) use and a reduced risk of AD and dementia, whereas estrogen-progestogen therapy (EPT) was associated with more variable outcomes. However, existing studies are heterogenous, and conventional endpoints might not adequately assess MHT's potential for AD prevention. Herein, several approaches are being discussed, and the case is being made for utilizing AD biomarkers for assessment of early, AD-specific outcomes in relation to MHT use. From a clinical standpoint, findings that MHT may lower dementia risk warrant consideration as existing therapies like acetylcholinesterase inhibitors and memantine lack preventative efficacy, and vaccines for primary or secondary prevention are not yet available. MHT-associated risks, including breast cancer, stroke and venous thromboembolism, are generally considered rare (<10 events/10 000 women). Overall, the literature supports renewed research interest in evaluating MHT as a female-specific, time-sensitive approach for AD risk reduction, which is key to applying cumulated data in clinical decision making concerning AD prevention.

People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, and the increased risk of MCI and AD is associated with the lack of estrogen during menopause. Previous studies have shown that Tiao Geng Decoction (TGD) may have antioxidant and anti apoptotic properties, which may prevent neurodegenerative diseases. However, whether TGD is effective in improving mild cognitive impairment due to postmenopausal estrogen deficiency and its potential pharmacological mechanisms remain unclear. The aim of this study was to investigate the possible pharmacological mechanisms of TGD in preventing postmenopausal MCI. We utilized RNA-seq technology to screen for differentially expressed genes (DEGs) and enrichment pathways in the hippocampal tissue of different groups of mice. Additionally, we adopted single-cell sequencing technology to study the cell types of Alzheimer's disease (AD) group and Normal Control (NC) group, the differential marker genes of each cell subgroup, and the GO enrichment analysis of each cell type. Both RNA sequencing and single-cell sequencing results showed a significant correlation between TGD and NF-κb pathway in improving mild cognitive impairment in postmenopausal women. The experimental verification results showed that the spatial learning and memory abilities of APP/PS1 model mice were weakened after ovariectomy, and the reproductive cycle on vaginal smears was in the interphase of diestrus. The levels of serum E2, and P-tau181 in mice were significantly down regulated, while the levels of brain tissue homogenate A β 42, IL-1 β, and IL-18 were significantly up-regulated, indicating successful modeling. Combining Western blotting, RT-qPCR, and transmission electron microscopy analyses, it was found that the low estrogen environment induced by oophorectomy can activate the NF-κb signaling pathway, activate the expression of NLRP3 inflammasome and A β secretase BACE1, and induce neuroinflammatory damage in hippocampal astrocytes. These results conform to the modeling characteristics of MCI. After TGD intervention, the spatial learning and memory abilities of MCI mice were significantly improved. The pharmacological validation results indicated that high concentration doses of TGD had a more significant effect on MCI. Subsequently, we used high concentration TGD (0.32 g/ml) as the traditional Chinese medicine group for further validation, protein blotting and RT-qPCR results indicated that TGD can effectively stimulate the secretion of ER α and ER β, inhibit the NF-κb pathway, downregulate BACE1, and inhibit the expression of NLRP3 inflammasome related proteins. In addition, the immunofluorescence results of hippocampal astrocytes showed that TGD can effectively facilitate the expression of AQP1 and significantly lower the sedimentation of A β compared with the model group. Our research suggests that there is a high correlation between a low estrogen environment and the occurrence and development of MCI. TGD may regulate the ERs/NF - κ b/AQP1 signaling pathway, promote estrogen secretion, activate AQP1, reduce A β deposition, reverse MCI neuroinflammatory injury, improve mild cognitive impairment, and prevent the occurrence of AD. This study revealed for the first time that TGD may be a potential new alternative drug for preventing and improving menopausal MCI.

GnRH is traditionally recognized as the central regulator of reproduction through its pulsatile secretion, which governs the hypothalamic-pituitary-gonadal axis. However, recent evidence has highlighted its broader role in brain development and function, including in cognitive and higher intellectual processes. GnRH production follows distinct phases, from its early activation during minipuberty-the first postnatal activation of GnRH neurons during the infantile period-, its reactivation and stabilization starting at puberty, and its eventual decline with age and the loss of gonadal steroid feedback. This evolution depends on the establishment, maturation and activation of GnRH neurons, a complex process regulated by the cellular and molecular environment of these neurons, including multiple neuronal and glial types as well as a minipubertal "switch" in gene expression, the perturbation of which may have long-term or delayed consequences for both reproductive and cognitive function. The cognitive role of GnRH may be related to its recently revealed involvement in maintaining myelination and synaptic plasticity, whereas disruptions in its finely tuned rhythmic secretion, either age-related or pathological, are associated with cognitive decline and neurodegenerative disorders. Restoring physiological GnRH levels and pulsatility can reverse age-related cognitive decline and improve sensory functions even in adulthood, suggesting a mobilization of the "cognitive reserve" in both animal models and human patients. This review highlights recent advances in our understanding of the GnRH system and the therapeutic potential of pulsatile GnRH therapy to mitigate age-related cognitive decline and neurodegenerative processes.

Changes in verbal memory have been reliably reported across the menopause transition. To understand the role of endogenous estrogens in verbal memory performance, this study assessed the associations of endogenous estradiol and estrone with brain network connectivity during a verbal memory fMRI task.

Determine associations of endogenous estrogens with memory systems in the postmenopausal brain and evaluate clinical significance.

In the MsBrain cohort (n = 199, mean age 59.3 ± 3.9 years, 83.9% White), we examined the cross-sectional association of serum estradiol (E2) and estrone (E1), measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), during a functional magnetic resonance imaging (fMRI) task of word encoding and recognition. To characterize the clinical significance of those associations, we examined the magnitude of activation in relation to a neuropsychological measures of memory and affect.

Endogenous E2 was positively associated with activation in temporal and frontal cortices during encoding and negatively associated with one prefrontal region during recognition (P < .05). Activation in the left inferior frontal gyrus was associated with memory performance (β [SE] = 0.004 [0.002]; P < .05), and anxiety (β [SE] = -0.100 [0.050]; P < .05). The left middle frontal gyrus was associated with memory performance (β [SE] = 0.006 [0.002]; P < .01), depression, and anxiety. The left superior temporal gyrus (STG) was associated with depression (β [SE] = -0.083 [0.036]; P < .05) and anxiety (β [SE] = -0.134 [0.058]; P < .05). E1 was positively associated with activation in a range of brain areas including bilateral STG and right superior frontal gyrus during encoding (P < .05). Activation of the left insula and precentral gyrus were associated with symptoms of depression and anxiety. None related to memory.

The function of brain areas critical to memory performance varies with estrogen levels in the postmenopause, even though those levels are low. Higher levels of E2 may facilitate memory performance through enhanced function of temporal and frontal cortices during encoding of verbal material.

Sex and sex hormones are thought to influence multiple sclerosis (MS) through effects on inflammation, myelination and neurodegeneration, and exogenous hormones have been explored for their therapeutic potential. However, our understanding of how sex hormones influence MS disease processes and outcomes remains incomplete. Furthermore, our current knowledge is derived primarily from studies that focus exclusively on cisgender populations with exclusion of gender-diverse people. Gender-affirming hormone therapy comprising exogenous sex hormones or sex hormone blocking agents are commonly used by transgender and gender-diverse individuals, and it could influence MS risk and outcomes at various stages of disease. A better understanding of the impact and potential therapeutic effects of both endogenous and exogenous sex hormones in MS is needed to improve care and outcomes for cisgender individuals and, moreover, for gender-diverse populations wherein an evidence base does not exist. In this Perspective, we discuss the effects of endogenous and exogenous sex hormones in MS, including their potential therapeutic benefits, and examine both established sex-based dimorphisms and the potential for gender-diverse dimorphisms. We advocate for future research that includes gender-diverse people to enhance our knowledge of the interplay of sex and sex hormones in MS, leading to the development of more effective and inclusive treatment strategies and improvement of care for all individuals with MS.

Findings concerning the effects of hormone therapy (HT) on cognition and dementia are mixed, with some trials suggesting increased harm at older ages. Personality, like cognition, changes with dementia, but no clinical trials to date have examined the effects of HT on personality traits. This study aimed to determine the effects of HT on personality traits in older men and women.

Secondary data analysis was performed from randomized, double-blind, placebo-controlled cross-over studies of menopausal HT in women and testosterone therapy (TT) in men. Participants were community-dwelling cognitively normal adults (mean age = 75.2 years), including 29 men and 22 women. Three months of hormone intervention (for women, 0.625 mg/day conjugated equine estrogen with or without 2.5 mg/day medroxyprogesterone acetate; for men, 200 mg intramuscular testosterone enanthate every 2 weeks) were crossed over with 3 months of identical placebo with a 3-month washout between intervention phases. The main outcome measure was neuroticism and conscientiousness personality domains and facets assessed with the Revised NEO Personality Inventory (NEO-PI-R) after the active and placebo intervention phases.

In linear mixed-effect models, HT in women decreased conscientiousness (p < 0.01) and the conscientiousness facet of achievement striving (p < 0.01), and increased vulnerability, a facet of neuroticism (p < 0.05). Testosterone in men decreased conscientiousness (p < 0.05) and the conscientiousness facet of dutifulness (p < 0.05), and increased vulnerability (p < 0.05).

In a preliminary study of healthy older adults, HT and TT formulations produced adverse changes in vulnerability and conscientiousness facets that parallel personality changes in dementia.

Commentary on: Nerattini M, Jett S, Andy C, et al Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia. Front Aging Neurosci. 2023;15:1260427. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's,University of London, UK.

Two thirds of Alzheimer's disease (AD) patients are female. Genetic and chronic health risk factors for AD affect females more negatively compared to males.

This exploratory multimodal neuroimaging study aimed to examine sex differences in cognitively unimpaired older adults on: (1) amyloid-β via 18F-AV-45 Florbetapir PET imaging, (2) neurodegeneration via T1 weighted MRI volumetrics, (3) cerebral blood flow via ASL-MRI. We identified AD risk factors including genetic (APOE genotype status) and health markers (fasting glucose, mean arterial pressure, waist-to-hip ratio, and android and gynoid body fat) associated with neuroimaging outcomes for which we observed sex differences.

Participants were sedentary, amyloid-β positive older adults (N = 112, ages 65-87 years) without evidence of cognitive impairment (CDR = 0).

Multivariate analysis of covariance models adjusted for intracranial volume, age, and years of education demonstrated lower volume (F (7, 102) = 2.67, p = 0.014) and higher blood flow F (6, 102) = 4.25, p =<0.001) among females compared to males in regions of interest connected to AD pathology and the estrogen receptor network. We did not observe sex differences in amyloid-β levels. Higher than optimal waist to hip ratio was most strongly associated with lower volume, while higher android fat percentage and APOE ε4 carrier status were most strongly associated with higher blood flow among female participants.

Findings suggest genetic and chronic health risk factors are associated with sex-specific AD neuroimaging biomarkers. Underlying sex-specific biological pathways may explain these findings. Our results highlight the importance of considering sex differences in neuroimaging studies and when developing effective interventions for AD prevention and risk reduction.

Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial.

The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline.

In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Menopause is a physiological period characterized by the cessation of ovarian activity. Sequential changes during this transition affect multiple systems, including the brain. Sixty percent of women experience cognitive impairment. The objective of this review is to show the neuroprotective effect of hormone replacement therapy (HRT) through the different scales and whether there is a benefit of this in women.

A search was conducted in six databases. Eligibility criteria included women within 10 years of menopause, receiving HRT controlled with placebo, studies lasting more than 6 months and women without a history of chronic underlying pathology.

A total of nine randomized controlled trials met the inclusion criteria. Regarding memory, two studies reported better performance of HRT with a significant odds ratio (OR) of 0.67; regarding attention, one study reported potential improvement in women receiving HRT with a significant OR of 0.87; and neuroimaging assessment found an increase in ventricular volume compared to placebo over a 3-year period.

The early initiation of menopausal HRT in healthy women appears to yield a positive effect on certain cognitive aspects, such as attention and cortical volume in the central nervous system. These findings should be confirmed through future prospective studies.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17β-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Mild cognitive impairment may be caused by pathophysiological changes occurring decades prior to symptom development. It has been hypothesised that oestrogen can prevent such changes. We aimed to investigate the association between postmenopausal hormone therapy and cognition in Danish female twins and to examine differences in this association before and after publication of the findings from the Women's Health Initiative study in 2002.

This study includes cognitive assessment of 4510 twins aged 50+ years. Information on hormone therapy was obtained through Danish health registries. The association between current hormone therapy use and cognition was analysed in twins aged 50+ using both cross-sectional, intrapair and longitudinal analysis, adjusting for age, education, social class, and unobserved familial confounding.

Cross-sectionally, systemic HT users aged 70+ had a significantly lower cognitive function than non-users, whereas systemic HT users aged 50-69 did not differ from non-users before 2002. Longitudinal data in younger twins aged 50-69 showed a significantly lower cognitive function in systemic HT users after 2002 compared to non-users. Systemic HT users aged 70+ showed that the lower cognitive function was most explicit before 2002, whereas after 2002 the cognitive function was closer to non-users. Twins aged 50-69 who changed from systemic HT to local HT after 2002, or dropped it altogether, performed cognitively better.

Our findings cautiously indicate a change in the association between cognition and hormone therapy use after 2002, which suggests an alteration in the hormone therapy user profile in the wake of the 2002 WHI publication.

Brain fog, referring to menopause-related subjective cognitive difficulties, is common in midlife women. Longitudinal studies find small but reliable declines in objective memory performance as women transition into perimenopause, and these are not explained by advancing age alone. When memory declines occur, performance levels remain within normal limits for all but a very small number of women. Women's experience of brain fog extends beyond memory complaints, reflecting the negative effect on a broad range of cognitive abilities. Clinicians can counsel women about how menopause symptoms, estrogen, hormone therapy, and modifiable risk factors (eg, hypertension, sedentary lifestyle) can influence cognitive health.

The effects on the brain of hormone therapy after the onset of menopause remain uncertain. The effects may be beneficial, neutral, or harmful. We provide a conceptual review of the evidence.

We 1) provide a brief history of the evidence, 2) discuss some of the interpretations of the evidence, 3) discuss the importance of age at menopause, type of menopause, and presence of vasomotor symptoms, and 4) provide some clinical recommendations.

The evidence and the beliefs about hormone therapy and dementia have changed over the last 30 years or more. Five recent observation studies suggested that hormone therapy is associated with an increased risk of dementia, and the association appears not to change with the timing of initiation of therapy. These harmful associations may be explained by a causal effect of hormone therapy on the brain or by several confounding mechanisms. We suggest that the use of hormone therapy should be customized for different subgroups of women. It may be important to subgroup women based on age at onset of menopause, type of menopause, and presence or absence of vasomotor symptoms. In addition, the effects may vary by type, dose, route, and duration of administration of estrogens and by the concurrent use of progestogens.

The relation of hormone therapy with the risk of dementia is complex. Hormone therapy may have beneficial, neutral, or harmful effects on the brain. Hormone therapy should be guided by the clinical characteristics of the women being treated.

Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Significant scientific research has been conducted concerning menopausal syndrome(MPS), yet few bibliometric analyses have been performed. Our aim was to recognise the 100 most highly cited published articles on MPS and to analytically evaluate their key features.

To identify the 100 most frequently cited articles, a search was conducted on Web of Science using the term 'menopausal syndrome'. Articles that matched the predetermined criteria were scrutinised to obtain the following data: citation ranking, year of publication, publishing journal, journal impact factor, country of origin, academic institution, authors, study type, and keywords.

The publication period is from January 1, 2000, to August 31, 2022. The maximum number of citations was 406 and in 2012. The median citations per year was 39.70. Most of the articles focused on treatment and complications. These articles were published in 36 different journals, with the Journal of MENOPAUSE having published the greatest number (14%). Forty-eight articles (48%) were from the United States, with the University of Pittsburgh being the leading institute (9%). Joann E. Manson was the most frequent first author (n = 6). Observational studies were the most frequently conducted research type (n = 53), followed by experimental studies (n = 33). Keyword analysis identified classic research topics, including genitourinary syndrome of menopause, bone mineral density (BMD), and anti-mullerian hormone (AMH) loci.

Using bibliometrics, we conducted an analysis to identify the inadequacies, traditional focal points, and potential prospects in the study of MPS across current scientific areas. Treatment and complications are at the core of MPS research, whereas prediction and biomarkers have less literature of high quality. There is a necessity for innovative analytical metrics to measure the real effect of these papers with a high level of citation on clinical application.

The Thai Menopause Society is an academic organization consisting of healthcare professionals engaged in menopause medicine. The position statement was first issued in 1994 and updated in 2003 and 2023. Herein, we reviewed the important updates of the 2023 position statement on menopausal hormone therapy (MHT) as an international reference for healthcare professionals in Thailand. An advisory panel of clinicians and research experts in the field of menopause reviewed the recommendation of published International Consensus Statements and updated the evidence using the MEDLINE database through PubMed. The evidence-based information and relevant publications were assessed, and a consensus on recommendations was subsequently achieved using the level of evidence to determine the recommendation strength and evidence quality. MHT remains the most effective treatment for vasomotor symptoms and genitourinary syndromes of menopause even after 20 years. Additionally, it is effective in preventing bone loss and fractures in postmenopausal women. The cardiovascular risk of MHT increased in women who initiated MHT after 60 years of age. Hormone therapy should be individualized following the hormone type, dose, administration route, use duration, and progestogen inclusion. The necessary pretreatment evaluation and appropriate follow-up recommendations were added for improved MHT standard care. The updated 2023 Clinical Practice Guideline on MHT is useful for gynecologists, general physicians, endocrinologists, and other healthcare professionals in treating menopausal women receiving hormone therapy in Thailand.

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 joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in the APOE region containing TOMM40, APOE, and APOC1 genes with P < 5 × 10-8 between APOE ε4 carriers and non-carriers in brain or blood. In brain, the most significant CpG site hypomethylated in ε4 carriers compared to non-carriers was from the TOMM40 in the total sample, while most of the evidence was derived from AD cases. However, the CpG site was not significantly modulating expression of these three genes in brain. Three CpG sites from the APOE were hypermethylated in APOE ε4 carriers in brain or blood compared in ε4 non-carriers and nominally significant with APOE expression in brain. Three CpG sites from the APOC1 were hypermethylated in blood, which one of the 3 CpG sites significantly lowered APOC1 expression in blood using all subjects or ε4 non-carriers. Co-methylation network analysis in blood and brain detected eight methylation networks associated with AD and APOE ε4 status. Five of the eight networks included genes containing network CpGs that were significantly enriched for estradiol perturbation, where four of the five networks were enriched for the estrogen response pathway. Our findings provide further evidence of the role of APOE genotype on methylation levels associated with AD, especially linked to estrogen response pathway.

This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS).

KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits.

Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance.

There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Given the potential for exogenous hormones to influence risk and course of MS, this narrative review aims to summarize current knowledge from observational and interventional studies of exogenous hormones in humans with MS.

Large randomized clinical trials for combined oral contraceptives and estriol both show modest effect on inflammatory activity, with the latter showing potential neuroprotective effect. After fertility treatment, large actively treated cohorts have not confirmed any elevated risk of relapse. Preclinical data suggest that androgens, selective estrogen receptor modulators (SERMs), and selective androgen receptor modulators (SARMs) may be neuroprotective but clinical data are lacking. Gender affirming treatment, particularly estrogen in trans-women, could possibly be associated with elevated risk of inflammation. For women with MS entering menopause, hormone therapy appears safe during the appropriate menopausal window, but its long-term effects on neuroprotection are unknown. Exogenous hormones, used in varied doses and for diverse indications, have variable effects on MS risk, inflammatory activity, and neuroprotection. Large randomized trials are needed before it is possible to determine the true effect of exogenous hormones in a condition as complex as MS.

Few studies have comprehensively examined the impact of reproductive factors (i.e., reproductive window, parity, hormonal contraception [HC], and menopausal hormone therapy [MHT]) on global and domain-specific cognition in later life.

We studied a population-based sample of 2458 women (median age 74.2 years) residing in Olmsted County, Minnesota; participants underwent a clinical evaluation and comprehensive cognitive testing.

The length of a woman's reproductive window was not associated with cognition. Higher parity was associated with greater cognitive decline in all domains. Ever HC use was associated with less decline in all domains. Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial; results were driven by women who initiated MHT 5 or more years after menopause. Additional adjustments for APOE and vascular-related covariates did not attenuate the results.

Multiple reproductive risk factors are associated with cognitive decline in later life.

The length of a woman's reproductive window was not associated with cognition longitudinally. Greater parity was associated with greater cognitive decline longitudinally. Ever HC use was associated with less decline in global cognition and all domain-specific z-scores longitudinally (all p < 0.01). Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial longitudinally (all p < 0.01). The greatest cognitive decline was among women who initiated MHT more than 5 years after menopause.

There is a continued debate on whether menopausal hormone therapy (MHT) protects women against Alzheimer's disease (AD). It is also unclear whether phytoestrogen could be an alternative treatment for AD.

To investigate whether mixed study findings may be due to differences in age at initiation of MHT and duration of prescription of different types of MHT using meta-analyses.

After a systematic literature search, meta-analyses were carried out using Cochrane Revman 5.4.1.software including data from large nationwide studies of registered medically diagnosed AD and prescribed MHT. These analyses were stratified for duration and type of treatment, by age at start of prescription of therapy. Insufficient quality data were available for phytoestrogen treatment and AD meta-analyses.

A total of 912,157 women were included from five registries, of whom 278,495 had developed AD during follow-up. Meta-analyses suggested a small increased AD risk after 5-10 years prescription of combination MHT regardless of age, and over 10 years only in women younger than 60 years of age. No association was seen for estrogen alone for women younger than 60 years of age, but AD risk did increase for women over 60 years of age for up to 5 years of MHT prescriptions.

Combination MHT should probably be prescribed for less than 5 years after menopause to reduce risk for AD, while estrogen alone should not be prescribed to women over 60. For phytoestrogen, small treatment trials suggested some benefit of tempeh (fermented soy), which should be investigated further.

The use of menopausal hormone therapy (MHT) has declined due to concerns about its potential side effects. However, its pivotal role in managing postmenopausal osteoporosis is gaining increased recognition. In this article, we explore how MHT assists postmenopausal women in maintaining bone health and preventing fractures. Recent research indicates that MHT significantly reduces the risk of fractures in women. This benefit is evident regardless of a woman's bone mineral density or their use of progestogens. However, there is limited evidence suggesting that the skeletal benefits continue once the treatment is discontinued. Possible complications of MHT include heart attacks, clots, strokes, dementia, and breast cancer. The most suitable candidates for MHT are women who have recently entered menopause, are experiencing menopausal symptoms, and are below 60 years of age with a minimal baseline risk of adverse events. The treatment is available to those who meet these criteria. For women undergoing premature menopause, MHT can be considered as a means to protect bone health, especially if initiated before menopause or if accelerated bone loss is documented soon after menopause. Such decisions should be made after evaluating individual risk factors and benefits.

Despite a large preclinical literature demonstrating neuroprotective effects of estrogen, use of menopausal hormone therapy (HT) for Alzheimer's disease (AD) risk reduction has been controversial. Herein, we conducted a systematic review and meta-analysis of HT effects on AD and dementia risk.

Our systematic search yielded 6 RCT reports (21,065 treated and 20,997 placebo participants) and 45 observational reports (768,866 patient cases and 5.5 million controls). We used fixed and random effect meta-analysis to derive pooled relative risk (RR) and 95% confidence intervals (C.I.) from these studies.

Randomized controlled trials conducted in postmenopausal women ages 65 and older show an increased risk of dementia with HT use compared with placebo [RR = 1.38, 95% C.I. 1.16-1.64, p < 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20-2.25, p = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92-1.54, p = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64-0.95, p = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70-0.94, p = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77-0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775-1.069, p = 0.251]. Stratified analysis of pooled estimates indicates a 32% reduced risk of dementia with midlife ET [RR = 0.685, 95% C.I. 0.513-0.915, p = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474-1.266, p = 0.309]. Late-life HT use was associated with increased risk, albeit not significant [EPT: RR = 1.323, 95% C.I. 0.979-1.789, p = 0.069; ET: RR = 1.066, 95% C.I. 0.996-1.140, p = 0.066].

These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for activating and maintaining the function of the hypothalamic-pituitary-gonadal axis, which controls the onset of puberty and fertility. Two recent studies suggest that, in addition to controlling reproduction, the neurons in the brain that produce GnRH are also involved in the control of postnatal brain maturation, odor discrimination, and adult cognition. This review will summarize the development and establishment of the GnRH system, with particular attention to the importance of its first postnatal activation, a phenomenon known as minipuberty, for later reproductive and nonreproductive functions. In addition, we will discuss the beneficial effects of restoring physiological (ie, pulsatile) GnRH levels on olfactory and cognitive alterations in preclinical Down syndrome and Alzheimer disease models, as well as the potential risks associated with long-term continuous (ie, nonphysiological) GnRH administration in certain disorders. Finally, this review addresses the intriguing possibility that pulsatile GnRH therapy may hold therapeutic potential for the management of some neurodevelopmental cognitive disorders and pathological aging in elderly people.

Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.

Understanding the role of both menopausal hormone therapy (MHT) along with non-hormonal options for the treatment of vasomotor symptoms, sleep disruption, and genitourinary symptoms after menopause is critical to the health of women during middle and later life. Recent updates to the evidence for the treatment of menopausal symptoms pertaining to both hormonal and non-hormonal therapies as well as updated guidance from specialty societies can help guide clinicians in their treatment of women going through natural menopause or with estrogen deficiencies due to primary ovarian insufficiency or induced menopause from surgery or medications. The objective of this narrative review is to provide clinicians with an overview of MHT for the use of menopausal symptoms in women, incorporating updated primary evidence for risk versus benefit profiles, recent specialty society recommendations, and alternative, non-hormonal options. In this review, we summarize literature on the use of MHT for menopause-related symptomatology including options for formulations and dosages of MHT, non-hormonal treatment options, and the risk-benefit profile of MHT including long-term health consequences (eg, cardiovascular disease, cognitive decline, venous thromboembolism, and fracture risk). Finally, we highlight areas in which future research is needed to advance care of women after menopause. In summary, both hormonal (MHT) and non-hormonal options exist to treat symptoms of menopause. There is strong evidence for safety and effectiveness of MHT for the treatment of vasomotor symptoms among women who are less than 60 years of age, less than 10 years since menopause, and without significant cardiometabolic comorbidities. For others, treatment with hormonal versus non-hormonal therapies can be considered based on individual risk profiles, as well as other factors such as drug formulation, therapeutic goals, and symptom severity.

Reviewing the research presented in this article, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex and gender differences in Alzheimer's dementia (AD) are due to differences in longevity, survival bias, and comorbidities. Medical, genetic, psychosocial, and behavioral factors, in addition to hormonal factors, can differentially affect the risk and progression of AD in women versus men. Further, evaluation of sex differences in AD progression and the trajectory of change in cognitive function, neuroimaging, cerebrospinal fluid (CSF), and blood-based biomarkers of AD is needed. Finally, identifying sex differences in AD biomarkers and change across the lifespan is critical for the planning of prevention trials to reduce the risk of developing AD.

Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]).

Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene.

During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

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.

The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.

The analysis used baseline data from participants in the European Prevention of Alzheimer's Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.

APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= -0.555, p=0.035) and left hippocampal volumes (standardized β= -0.577, p=0.028) only in APOE4 carriers.

HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group.

Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 μg/day transdermal 17β (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17β-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty.

All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17β-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time.

In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation.

NCT00154180, NCT00623311.

Recent high-profile failures of Alzheimer disease treatments at the clinical trial stage have led to renewed efforts to identify and test novel interventions for Alzheimer disease and related dementias (ADRD). In this Perspective, we highlight the importance of including well-designed observational studies as part of these efforts. Observational research is an important cornerstone for gathering evidence on risk factors and causes of ADRD; this evidence can then be combined with data from preclinical studies and randomized controlled trials to inform the development of effective interventions. Observational study designs can be particularly beneficial for hypothesis generation, posing questions that are unethical or impractical for a trial setting, studying life-course associations, research in populations typically not included in trials, and public health surveillance. Here, we discuss each of these situations in the specific context of ADRD research. We also highlight novel approaches to enhance causal inference and provide a timely discussion on how observational epidemiological studies help provide a bridge between preclinical studies and successful interventions for ADRD.

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.

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.