Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia.

Introduction: 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. Methods: 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. Results: 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]. Discussion: These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.

Psychosocial well-being during the COVID-19 pandemic among women with and without breast cancer.

OBJECTIVE: Treatment delays in combination with general social distancing practices to reduce transmission may have negative impacts on the mental health of women with breast cancer who may need more social and emotional support. We sought to elucidate the psychosocial effects of the COVID-19 pandemic among women with and without breast cancer in New York City. METHODS: We conducted a prospective cohort study among women aged 18+ across the spectrum of breast health care at New York Presbyterian (NYP)-Weill Cornell, NYP-Brooklyn Methodist Hospital and NYP-Queens. Women were contacted between June and October 2021 to assess their self-reported depression, stress, and anxiety during the COVID-19 pandemic. We compared women who were recently diagnosed, those with a history of breast cancer, and women without cancer whose other health visits were delayed during the pandemic. RESULTS: There were 85 women who completed the survey. Breast cancer survivors (42%) were the least likely to report a delay in care due to COVID compared to breast cancer patients who were recently diagnosed (67%) and women without cancer (67%). Compared to women without cancer and breast cancer survivors, women recently diagnosed with breast cancer reported higher levels of anxiety and depression with a statistically significant difference in perceived stress. CONCLUSIONS: Our findings highlight the need to identify and risk-stratify patients facing a new breast cancer diagnosis in and around the COVID-19 pandemic who may benefit from additional resources to mitigate the adverse impacts of the pandemic and a breast cancer diagnosis on psychosocial health.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

Introduction: In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. Methods: We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-ß (Aß) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. Results: FSH levels were positively associated with Aß load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aß load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Discussion: Increasing serum gonadotropin levels, especially FSH, are associated with higher Aß load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

Endogenous and Exogenous Estrogen Exposures: How Women's Reproductive Health Can Drive Brain Aging and Inform Alzheimer's Prevention.

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 17ß-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.

Soluble T cell immunoglobulin mucin domain 3 (sTim-3) in maternal sera: a potential contributor to immune regulation during pregnancy.

OBJECTIVE: The immune checkpoint inhibitor, membrane-bound T cell immunoglobulin mucin domain 3 (Tim-3), binds to galectin-9 (gal-9) and promotes immune tolerance during pregnancy. Soluble Tim-3 (sTim-3) competes with Tim-3 for binding to gal-9 and modulates its activity. Our objective was to evaluate the influence of sTim-3 on immune responses and outcome in pregnant women. STUDY DESIGN: Peripheral blood from 71 pregnant women was separated into mononuclear cell (PBMC) and plasma fractions. The PBMCs were lysed and tested for Tim-3 by ELISA. Plasma was assayed for sTim-3, gal-9, tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and the stress-inducible 70 kDa heat shock protein (hsp70) by enzyme-linked immunosorbent assay (ELISA). Correlations were analyzed by the Spearman rank correlation test. RESULTS: The higher the sTim-3 level in plasma the lower was the PBMC Tim-3 concentration (p = .0135), suggesting that sTim-3 results from the release of membrane-bound Tim-3. Plasma sTim3 levels were positively correlated with levels of gal-9 (p < .0001), TNF-α (p = .0071) and hsp70 (p = .0144), but not with IL-10. The sTim-3 level was positively associated (p = .0276) with gestational age at delivery. There was no association between sTim-3 and gestational age at sample collection, maternal age, gravidity, parity or body mass index. CONCLUSION: The release of Tim-3 from membranes and sTim-3 reacting with gal-9 may increase proinflammatory immunity and the stress response. The release of sTim-3 from lymphoid cells into the circulation and its binding to gal-9 may modulate Tim-3-mediated activity and help optimize immune regulation during pregnancy.