Figure - available from: Human Brain Mapping
This content is subject to copyright. Terms and conditions apply.
Estrogen receptors are found throughout the brain and are predominantly present in the cerebellum, ventral tegmental area (VTA), hippocampus, amygdala, and frontal cortex; as well as in the raphe nuclei of the midbrain (Barth et al., 2015). There is a greater concentration of estrogen‐alpha receptors in regions such as the amygdala and hypothalamus whereas estrogen‐beta receptors dominate in the hippocampus. More equal representation exists in areas such as the thalamus and the cerebellum (Hedges, Ebner, Meisel, & Mermelstein, 2012; Osterlund & Hurd, 2001). Adapted with permission from Dr. Julia Sacher (Barth et al., 2015)
Source publication
Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors...
Similar publications
Isoflavonoids are phytoestrogenic compounds found mainly in plants from the Fabaceae family and also in soy-based foods. Isoflavonoids exhibit (anti)estrogenic effects, acting on estrogen receptors due to the structural similarities with estrogenic hormones (17β-estradiol). The aim of our minireview is to highlight the pharmacokinetic and pharmacod...
Citations
... E2 and P4 modulate brain activity by binding to their respective receptors. E2 receptors (ERs) and P4 receptors (PRs) are distributed throughout cortical and subcortical structures, with the most dense expression found in the prefrontal cortex, hippocampus, amygdala, and cerebellum (6)(7)(8)(9)(10). The distribution of ERs/PRs underscores the widespread influence that these hormones have on brain structure and function. ...
Background
Ovarian hormones exert direct and indirect influences on the brain; however, little is known about how these hormones impact causal brain connectivity. Studying the female brain at a single time point may be confounded by distinct hormone phases. Despite this, the menstrual cycle is often overlooked. The primary objective of this pilot study was to evaluate resting-state causal connectivity during the early follicular and mid-luteal menstrual phases corresponding to low vs high estradiol and progesterone, respectively.
Methods
Fourteen healthy control females ( M = 20.36 years, SD = 2.02) participated in this study. Participants were scheduled for two resting-state electroencephalography (EEG) scans during their monthly menstrual cycle. A saliva sample was also collected at each EEG session for hormone analyses. Causal connectivity was quantified using information flow rate of EEG source data. Demographic information, emotional empathy, and sleep quality were obtained from self-report questionnaires.
Results
Progesterone levels were significantly higher in the mid-luteal phase compared to the early follicular phase ( p = .041). We observed distinct patterns of causal connectivity along the menstrual cycle. Connectivity in the early follicular phase was centralized and shifted posteriorly during the mid-luteal phase. During the early follicular phase, the primary regions driving activity were the right central and left/right parietal regions, with the left central region being the predominant receiver of activity. During the mid-luteal phase, connections were primarily transmitted from the right side and the main receiver region was the left occipital region. Network topology during the mid-luteal phase was found to be significantly more assortative compared to the early follicular phase.
Conclusions
The observed difference in causal connectivity demonstrates how network dynamics reorganize as a function of menstrual phase and level of progesterone. In the mid-luteal phase, there was a strong shift for information flow to be directed at visual spatial processing and visual attention areas, whereas in the follicular phase, there was strong information flow primarily within the sensory-motor regions. The mid-luteal phase was significantly more assortative, suggesting greater network efficiency and resilience. These results contribute to the emerging literature on brain-hormone interactions.
... In this study, rationalizing the effects of CAFF, AGO + CAFF, and QUET + CAFF by exploring the brainovarian crosstalk stems from multiple studies linking peripheral estrogenic signaling to cognition (Boyle et al. 2021;Russell et al. 2019) and seizure susceptibility (Pottoo et al. 2019;Reddy et al. 2021). Such an objective is also inspired by the established brain control over ovarian functions, such as that mediated by melatonin, which regulates reproduction in photoperiodic animals (Macchi and Bruce 2004) owing to its central gonadotropic activity (Romeu et al. 2011). ...
... This is consistent with a previous study in which AGO was administered at a higher dose (40 mg/kg) to a kainic acid-induced model of status epilepticus in rats, and the authors indicated that the anticonvulsant effect of AGO could occur, even if AGO did not exert a neuroprotective activity (Tchekalarova et al. 2019). Although, with prolonged AGO monotherapy, no overt EEG changes denoted a better cognitive state than controls, the increased brain E2, together with enhanced cortical E2Rα immunoreactivity, associated with a similar cortical microstructure as the control, support previous studies highlighting the cognitive enhancing activity of both estrogenic signaling (Boyle et al. 2021) and AGO (Su et al. 2023). The role of estrogen in AGO-mediated cognitive amelioration has been demonstrated in ovariectomized rats (El-Khatib et al. 2020). ...
... Conformant to the neuroprotective role of estrogen (Bustamante- Barrientos et al. 2021;Simpkins et al. 2012), our study revealed that the number of degenerated cortical cells was negatively correlated to ovarian E2Rα. Such findings supported the implication of systemic estrogen in brain functions; therefore, hormonal replacement therapy could be employed for the treatment of some neurodegenerative disorders (Boyle et al. 2021;Brann et al. 2007;Russell et al. 2019). Given the pro-convulsant activity of E2 (Frank & Tyson 2020), the positive correlation between brain E2 and ovarian E2Rα detected herein highlights the anti-epileptogenic activity of CAFF, alone or combined with AGO or QUET, owing to reduced ovarian E2Rα. ...
Rationale
Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances.
Objectives
The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated.
Methods
Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17β-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed.
Results
CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2.
Conclusions
CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects.
... Like testosterone, estrogen has neuroprotective effects [58], including stimulating neurogenesis and synaptogenesis [59][60][61] and protecting against amyloid-beta plaque deposition [62]. Another similarity to testosterone is evidence of an estrogen and APOE-ε4 interaction, where the deleterious effects of postmenopausal estrogen deficiency on the brain appear more robust in APOE-ε4 carriers compared to non-carriers [63][64][65]. Levels of circulating estradiol were not available ADNI, which precluded our ability to consider the role of estrogen in the present study, but examining both sex hormones and their relationship with APOE-ε4 may provide a clearer picture for our sex-specific results. ...
Background:
Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer's disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone's effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype.
Methods:
Five hundred and sixty one participants aged 55-90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language.
Results:
We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males.
Conclusions:
Findings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone's role in cognitive health.
... Multiple lines of evidence show that E2 directly affects structural and, with this, functional and behavioral trajectories in the brain throughout the lifetime of a female (9,27,(70)(71)(72). However, the available endogenous circulating E2 supply is not steady across the lifespan but varies not only with chronologic age but also within the reproductive period, as it fluctuates with the menstrual cycle, significantly increases during pregnancy, and then drops postpartum (73)(74)(75). ...
... During the transition period to full menopause and geripause, the body including the circuits of the brain must somehow adjust to the changing estrogenic milieu and eventually compensate for or adapt to hypoestrogenemia. It has become evident that a continual E2-deficient state recognized as post-menopause broadly and adversely impacts neural and behavioral functions especially those associated with the prefrontal cortex, hippocampus, and hypothalamus (9,19,27,(70)(71)(72). This may lead to or exacerbate a constellation of symptoms such as cognitive frailty, mood and sleep disturbances, vasomotor symptoms (VMS), as well as susceptibility to develop age-related neurodegenerative diseases, among them Alzheimer's disease-just to mention a few unpleasant consequences of the hypoestrogenic or estrogen-deficient aging female brain (39, 40, 74, 77, 78). ...
Sex steroids are essential for whole body development and functions. Among these steroids, 17β-estradiol (E2) has been known as the principal “female” hormone. However, E2’s actions are not restricted to reproduction, as it plays a myriad of important roles throughout the body including the brain. In fact, this hormone also has profound effects on the female brain throughout the life span. The brain receives this gonadal hormone from the circulation, and local formation of E2 from testosterone via aromatase has been shown. Therefore, the brain appears to be not only a target but also a producer of this steroid. The beneficial broad actions of the hormone in the brain are the end result of well-orchestrated delayed genomic and rapid non-genomic responses. A drastic and steady decline in circulating E2 in a female occurs naturally over an extended period of time starting with the perimenopausal transition, as ovarian functions are gradually declining until the complete cessation of the menstrual cycle. The waning of endogenous E2 in the blood leads to an estrogen-deficient brain. This adversely impacts neural and behavioral functions and may lead to a constellation of maladies such as vasomotor symptoms with varying severity among women and, also, over time within an individual. Vasomotor symptoms triggered apparently by estrogen deficiency are related to abnormal changes in the hypothalamus particularly involving its preoptic and anterior areas. However, conventional hormone therapies to “re-estrogenize” the brain carry risks due to multiple confounding factors including unwanted hormonal exposure of the periphery. In this review, we focus on hot flushes as the archetypic manifestation of estrogen deprivation in the brain. Beyond our current mechanistic understanding of the symptoms, we highlight the arduous process and various obstacles of developing effective and safe therapies for hot flushes using E2. We discuss our preclinical efforts to constrain E2’s beneficial actions to the brain by the DHED prodrug our laboratory developed to treat maladies associated with the hypoestrogenic brain.
... Additionally, we did not account for other lifestyle factors in this work such as physical activity, diet, and genetic variables and these data should be evaluated with respect to brain structure in future work. We also did not adjust for menopause, which has been related to visceral fat [50], in this investigation as we did not exclusively study our female sex participants as we have done so in prior work [51], though such questions are important for future work. Finally, while we did track atrophy with 3D T1 volumetric quantification, additional insights could have been obtained with advanced neuroimaging such as perfusion MRI and tractography. ...
... an AD model prevented neuronal loss in OVX rats 70 . While estrogen has been reported to have protective effects for cerebral endothelial cells, HRT has not had success in recent randomized clinical trials looking delaying the onset of AD 71 . Thus, HRT of estrogen may not be the solution perhaps because there are changes in estrogen receptors postmenopausal. ...
Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence on the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements both in vivo (acute cranial window vascular diameter) and ex vivo (pressure myography experiments), we measured lower myogenic tone responses in hippocampal arterioles from female than male mice. By using a combined surgical and pharmacological approach, we found myogenic tone in ovariectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity and expression of the small-conductance Ca2+-sensitive K+ (SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures.
... This study was conducted as part of the Cardiovascular Health Study (CHS), a multisite, population-based longitudinal study designed to study cardio-cerebrovascular diseases in adults aged ≥65 years (Boyle et al., 2021). A total of 5888 participants were recruited from communities beginning in 1989 and followed up for more than 20 years. ...
Objectives:
This study aimed to investigate the association between electrocardiogram (ECG) abnormalities and silent vascular brain injury as defined by cerebral magnetic resonance imaging (MRI) in a stroke-free community-based population.
Methods:
A total of 5888 participants were studied from the Cardiovascular Health Study (CHS), a prospective cohort of community-living older adults. Standard 12-lead ECGs measured prior to MRI scan were used. MRI scans were conducted at years 4-6 and 10-11. The primary outcome was presence of incident covert brain infarcts (CBIs) on the 2nd MRI examination, excluding previous CBIs and stroke occurrence. Secondary outcomes included white matter, ventricular, and sulcal atrophy on the 1st MRI. Logistic and multiple linear regression models were used to assess the relationship between ECG findings and silent vascular brain injury.
Results:
Left axis deviation before MRI scan was related to presence of incident CBIs (odds ratio [OR]: 1.45; 95% CI: 1.01-2.08, p = .047). A long QT interval was associated with severe white matter hyperintensity (OR: 1.36; 95% CI: 1.04-1.77, p = .024). Minor Q and QS waves with ST-T abnormalities were positively related to sulcal atrophy (β: 0.43, 95% CI: 0.06-0.81, p = .023).
Conclusions:
Our study found that ECG abnormalities were related to presence of CBIs, white matter hyperintensity, and sulcal atrophy on MRI in a stroke-free relderly population. Specifically, those with left axis deviation had an increased risk of presence of CBIs.
... Menopausal estrogen therapy (ET) improves the structural integrity of tissue, inducing neuronal growth and similar trophic effects. Several morphometric studies [25][26][27] reported that postmenopausal women who received the ET showed enhanced cognitive function and brain volume. A previous VBM study 28 showed that post-menopausal women receiving ET had larger cortical GM volumes than postmenopausal women without ET, especially in the hippocampus-amygdala complex and cerebral cortex. ...
... However, using conventional volume measurement, there were no significant differences between the two groups in total intracranial volume. [25][26][27] reported that estrogen increased the neutral effect or affected structural integrity in brain tissue, especially in the prefrontal, temporal, and parietal lobes. In the study, estradiol levels in pre-menopausal women were significantly higher than in post-menopausal women, while FSH was significantly lower. ...
... The serum estradiol level in MHT women, such as pre-menopausal women, was higher than that of noMHT women, while the FSH level was lower. These hormonal changes in MTH women were similar to previous studies [25][26][27] , demonstrating level values before and after hormone therapy. Compared to noMHT women, the increments in local GM volume observed in MHT women could be associated with protection or suppression of cell loss or/and cell shrinkage related to MHT treatment. ...
Menopausal hormone therapy (MHT) in women can reduce troublesome menopause symptoms and prevent cognitive decline. This cross-sectional study investigated the MHT-related effect on brain morphology and its association with sex hormones in menopausal women by using an optimized diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL)-based voxel-based morphometry (VBM) method. Twenty-one menopausal women without MHT (noMHT) and 20 menopausal women with MHT were included in this study. Magnetic resonance imaging data were processed using SPM 12 with DARTEL-based VBM whole brain analysis approach. A 2-sample t-test and analysis of covariance (ANCOVA) adjusting for age and total intracranial volume were used to compare GM volume between noMHT and MHT women. The association between MHT (treatment period, hormones levels) and brain volume variations were analyzed by Spearman correlation. MHT women showed significantly larger volumes of the superior/middle/inferior frontal gyri, hypothalamus, inferior temporal gyrus, parahippocampal gyrus, hippocampus, cerebellar cortex, postcentral gyrus, precuneus, angular gyrus, supplementary motor area, superior occipital gyrus, and precentral gyrus compared to the noMHT women. The volumes of the angular gyrus and hypothalamus in MHT women positively correlated with treatment period. On the other hand, the hypothalamic volume negatively correlated with FSH and LH levels, and the volumes of the inferior frontal gyrus, and angular gyrus negatively correlated with progesterone levels, respectively. MHT-treated women showed larger GM volume than noMHT women. The anatomical structures that showed greater volume in association with MHT included the deep brain areas, frontal, temporal, parietal, and occipital gyri.
... Multiple linear regression analyses were performed to investigate the relationship between female-specific factors (independent variable) and cognitive test scores (dependent variable). All models included the following additional independent variables known to influence reproductive history, hormone use and cognition: age, education, body mass index (BMI), Townsend deprivation index, and lifestyle score (Park and Reuter-Lorenz, 2009;Lovden et al., 2020;Boyle et al., 2021; see Supplementary Note S2 for details on Townsend deprivation index and lifestyle score). In addition, the analyses for reproductive span and age at menopause were corrected for use of HT, use of HC, history of bilateral oophorectomy and/or hysterectomy, and number of live births. ...
Introduction
Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer’s disease. While women’s health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women’s cognition later in life.
Methods
We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein ( APOE ) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function.
Results
A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen’s d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition.
Discussion
Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer’s disease is crucial for a better understanding of women’s brain health and to support women’s health care.
... Decreased estrogen levels before, during and after menopause can affect memory and cognitive function [292]. Alzheimer's disease (AD) is the most common neurodegenerative disorder, and female sex is a key risk factor for AD, especially in postmenopausal women [293]. ...
Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation.
Graphical Abstract
