The effect of hormone replacement therapy on cognitive function in healthy postmenopausal women: a meta‐analysis of 23 randomized controlled trials

Zhou, Huanhuan; Yu, Zengli; Luo, Lan; Xie, Fangfei; Wang, Yun; Wan, Zhongxiao

doi:10.1111/psyg.12768

Cited by 12 publications

(14 citation statements)

References 65 publications

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“…Similarly, an observational study showed that the introduction of HRT in midlife (age 48.7 years) was associated with a 26% reduced risk of dementia compared to 48% increased risk when HRT was initiated in later life (age 76 years) [80]. In a recent meta-analysis in healthy post-menopausal women, HRT use was associated with reduced global cognition, which was less evident for those younger than 60 years old [17]. Our results are consistent with these findings, with our findings specifically observing that this impact of early initiation is specific to APOE4 carriers.…”

Section: Discussionmentioning

confidence: 96%

“…A recent meta-analysis of 23 RCTs showed no impact of oral estrogen alone or CEE plus MPA on delayed memory scores, even at a younger age (<60 years), with an overall negative effect on global cognition. However, no sub-group analysis according to APOE genotype was carried out [17].…”

Section: Discussionmentioning

confidence: 99%

“…A recent meta-analysis showed that the negative effect of HRT on global cognition has been predominately tested in those >60years. In this meta-analysis, only two studies recruited participants <60years, with one showing no impact of oral estrogen on global cognition and the second showing a positive impact of CEE plus MPA on global cognition [17]. Limited recent, mainly preclinical, data has identified APOE genotype and age of HRT initiation as potential modulators of the HRT cognitive response [7,18,19].…”

Section: Introductionmentioning

confidence: 93%

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Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

et al. 2023

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Background 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. Methods 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. Results 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. Conclusion 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.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

et al. 2023

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“…Low bioavailable levels of estradiol in older women were associated with a higher risk of cognitive impairment 7 . However, results of randomized clinical trials that examined postmenopausal hormone therapy for prevention of cognitive decline have found no benefits 8,9 . These inconsistent findings could stem from different reasons including locally generated estrogen that affects brain function 10 above and beyond circulating estrogen.…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease

Oveisgharan

Yang

et al. 2023

Neurology

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Background:Lifetime risk of Alzheimer’s disease (AD) dementia is two-fold higher in women compared with men, and low estrogen levels in post menopause have been suggested as a possible contributor. We examined 3ERs (GPER1,ER2,ER1) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. While the study focus was on women, in a comparison we separately examinedERmolecular variants in men.Methods:Participants were followed for an average 10 years in one of two longitudinal clinical pathological studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests’ scores. Postmortem pathological assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangles count) and 8 non-AD pathology indices.ERmolecular genomic variants included genotyping and examiningERDNA methylation and RNA expression in brain regions including dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology.Results:Mean age of women (N=1711) at baseline was 78.0 (SD=7.7) years. In women,GPER1molecular variants had the most consistent associations with AD traits.GPER1DNA methylation was associated with cognitive decline, tau tangles density, and global AD pathology score.GPER1RNA expression in DLPFC was related to cognitive decline and tau tangles density. Other associations included associations ofER2andER1SNPs and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangles density in women. In men (N=651, average age at baseline: 77.4 (SD=7.3)), there were less robust associations betweenERmolecular genomic variants and AD cognitive and pathological traits. No consistent association was seen betweenERmolecular genomic variations and non-AD pathologies in either of sexes.Conclusion:ERDNA methylation and RNA expression, and to some extentERpolymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lower extent in men.

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“…Unfortunately, these trials were not successful. Previous randomized controlled trials (RCTs) tended to focus on hormones ( 44 , 45 ) and rarely considered hormone transporters such as SHBG. Our MR research systematically interpreted the relationship between SHBG and neurodegenerative diseases, extending traditional observational associations to gene-mediated causality.…”

Section: Discussionmentioning

confidence: 99%

Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study

Ou¹,

Liu²,

Wu³

et al. 2022

Ann Transl Med

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Background: Extensive observational studies have suggested an association between serum sex-hormone binding globulin (SHBG) and Alzheimer's disease (AD); however, causality remains unclear. Furthermore, the effects on other neurodegenerative diseases have been poorly investigated. We aimed to explore the causal effects of genetically predicted SHBG serum levels on common neurodegenerative diseases.Methods: A two-sample Mendelian randomization (MR) approach was used. Genetic variants of SHBG levels in the serum, detected using the chemiluminescent two-step sandwich immunoassay method, were identified from a genome-wide association meta-analysis from the UK Biobank (N=363,228). Summary-level data for AD, and other common neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were adopted from the corresponding large genome-wide association studies of individuals of European ancestry, which were either clinically or autopsy-diagnosed. Causal estimates were calculated using the inverse-variance weighted (IVW) method and several sensitivity methods (MR-Egger, weighted median, and weighted mode). Egger intercept, MR-PRESSO, and leave-one-out analyses were used to identify potential violations.Results: Genetically determined serum SHBG levels [odds ratio (OR IVW )=1.113, 95% CI: 1.019-1.215, P=0.017] were associated with an increased risk of ALS. This causal effect was confirmed using sensitivity analyses, including the MR-Egger (OR =1.229, 95% CI: 1.049-1.441, P=0.012), weighted median (OR =1.231, 95% CI: 1.077-1.406, P=0.002), and weighted mode (OR =1.235, 95% CI: 1.067-1.431, P=0.005) methods. No notable heterogeneity or directional pleiotropy was observed. However, leave-one-out analysis showed that rs9892297 drove the observed effects. There was no evidence that genetically predicted serum SHBG levels affect other neurodegenerative diseases, including AD, PD, MS, DLB, and FTD (all P>0.05).Conclusions: This MR analysis found that genetically determined serum SHBG was associated with an increased risk of ALS rather than AD, which is inconsistent with previous observational studies. This novel finding highlights the potential of SHBG in peripheral serum for ALS prevention. Further research into the effects of SHBG on other neurodegenerative diseases is required, especially because of the increased utilization of hormone therapy.

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The effect of hormone replacement therapy on cognitive function in healthy postmenopausal women: a meta‐analysis of 23 randomized controlled trials

Cited by 12 publications

References 65 publications

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease

Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study

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