Exercise and Cognitive Function in Peri- and Postmenopausal Women: Evidence from Human RCTs and Mechanistic Preclinical Studies

Article information

Exerc Sci. 2026;35(3):223-238

Publication date (electronic) : 2026 August 26

doi : https://doi.org/10.15857/ksep.2026.00045

Hunyoung Ha, BS^1,†, Siyun Kim, BS^2,†, Heehyun Shin, BS¹, Sewon Lee, PhD^3,4, Oh Sung Kwon, PhD^2,5, Kyeongho Byun, PhD^,3

¹Department of Human Movement Science, Incheon National University, Incheon, Korea

²Department of Kinesiology, College of Agriculture, Health and Natural Resources, University of Connecticut, Connecticut, United States

³Division of Sport Science, Sport Science Institute, Health Promotion Center, Incheon National University, Incheon, Korea

⁴Research Center of Brain Machine Interface, Incheon National University, Incheon, Korea

⁵Department of Orthopaedic Surgery & Center on Aging, University of Connecticut School of Medicine, Connecticut, United States

Corresponding author: Kyeongho Byun Tel: +82-32-835-8648 Fax: +82-32-835-0788 E-mail: kbyun21@inu.ac.kr

†H.H. and S.K. contributed equally to this work.

Received 2026 February 3; Revised 2026 April 28; Accepted 2026 May 8.

Abstract

Graphical Abstract

INTRODUCTION

Population aging has increased the burden of mid- and late-life health conditions through rising healthcare costs and caregiving demands. In women, the menopausal transition represents an important neuroendocrine event accompanied by substantial physical, psychological, and social changes [1-3]. Cognitive health is particularly consequential for functional independence and quality of life; many women report cognitive complaints during and after menopause across global cognitive function, executive function (e.g., attention, verbal fluency, working memory, and cognitive flexibility), and memory [3,4]. Although the nature and determinants of these difficulties are heterogeneous, they indicate the clinical and public health need to identify strategies that may protect cognitive health across the menopausal transition and later life.

Across the transition from pre- to peri- and post-menopause, circulating estrogen levels, particularly 17β-estradiol, decline and show pronounced variability, especially during perimenopause [5,6]. Estrogen has been implicated in neuroprotective processes relevant to cognition—including synaptic plasticity, neurotransmission, and cerebral energy metabolism, particularly within the hippocampus and prefrontal cortex [7]. Therefore, reductions in estrogen levels have been associated with declines in memory and executive function in some studies [4,8,9]. In parallel, menopausal hormonal changes are associated with less favorable cardiometabolic profiles and increased risk of type 2 diabetes mellitus [10,11]. Given the close coupling between vascular-metabolic health and brain structure and function, these systemic alterations may constitute additional pathways through which menopause influences cognitive trajectories [12,13]. Consequently, these neural and systemic changes support the evaluation of interventions that can address multiple mechanisms relevant to cognitive health.

Physical activity and structured exercise are potential non-pharmacological strategies with plausible mechanistic relevance. Meta-analytic evidence in sedentary older adults suggests that exercise (e.g., walking) can improve aspects of executive functions, including inhibitory control, and observational studies associate higher physical activity levels with slower cognitive decline and reduced mortality risk [14,15]. In broader older-adult populations, higher physical activity or cardiorespiratory fitness has been linked to better cognitive performance, and aerobic, resistance, and combined training programs (including multicomponent modalities) have demonstrated potential benefits for memory, attention, and executive function [16-18]. These effects are typically conceptualized as arising from convergent pathways, including cardiovascular and metabolic regulation, affective processes, sleep, and neuroplasticity-related signaling, which align with menopause-related vulnerabilities [19-23]. However, menopause-specific evidence remains comparatively limited and methodologically heterogeneous, limiting inferences regarding the conditions under which exercise is most likely to confer cognitive benefits and the mechanisms that may mediate such effects.

Interpretation is further limited by challenges inherent to human intervention research in menopausal women, including variability in cognitive endpoints, substantial heterogeneity in exercise prescriptions (modality, intensity, dose, and duration), and limited mechanistic measurement (e.g., hormonal profiles, inflammatory markers, and neuroplasticity-related indices). As a result, even when cognitive improvements are reported, mechanistic attribution to specific menopause-relevant pathways is often tentative. Preclinical models can address these mechanistic gaps: ovariectomized (OVX) or aged female animal models approximate key aspects of menopausal endocrine status and enable molecular and cellular investigations (e.g., synaptic plasticity, brain-derived neurotrophic factor (BDNF)-related signaling, and neuroinflammation) that are difficult to implement in humans. Importantly, animal studies should be viewed not as direct extensions of clinical efficacy but as complementary evidence that can refine biologically grounded hypotheses, reconcile inconsistencies, and strengthen causal plausibility. Given the heterogeneity across interventions, cognitive outcomes, and mechanistic assessments, a narrative synthesis is required to integrate human and preclinical evidence.

Accordingly, this narrative review synthesizes evidence from randomized controlled trials (RCTs) in peri- and postmenopausal women and evaluates the effects of aerobic, resistance, and combined exercise, and related cognitively engaging modalities (e.g., mind-body and dancebased interventions) on global cognition and domain-specific outcomes, with a focus on executive function and memory. We further examine whether outcomes vary by key prescription parameters, including intensity, duration, frequency, and timing with respect to menopausal stage. By integrating mechanistic findings from human studies with complementary evidence from OVX animal models, we propose a framework describing pathways through which exercise may support cognitive health during and after the menopausal transition and delineate priorities for future trials and practical exercise prescription aimed at cognitive protection.

METHODS

This narrative review aims to synthesize evidence from RCTs in peri-and postmenopausal women and to contextualize these findings with mechanistic insights derived from estrogen-deficit animal models. Specifically, we sought to (1) summarize how different forms of exercise, including aerobic, resistance, and combined modalities affect global cognition, executive function, and memory in women across the menopausal transition, and (2) describe the neurobiological pathways that may underlie these exercise-induced cognitive benefits by drawing on preclinical studies employing OVX or aged female animal models. By aligning clinical outcomes with experimentally identified mechanisms, this review provides an integrative framework for understanding how exercise may preserve or enhance cognitive health during menopause.

A targeted literature search was conducted in PubMed and Web of Science on December 14, 2025. The search strategy combined terms related to menopause, exercise, and cognition (e.g., “postmenopausal” OR “menopausal,” “exercise,” “cognitive functions,” and “cognition”). The initial search identified 2,050 records (PubMed: n=1,184; Web of Science: n=866). Of these, 453 records were removed during initial screening: 397 duplicates and 56 studies published prior to the year 2000. The remaining 1,597 records were screened for eligibility.

From these, 150 studies using animal models were identified and set aside for the preclinical component, leaving 1,447 human studies for further screening. At the title and abstract screening stage, 1,430 human studies were excluded, leaving 17 reports sought for retrieval. Of these, nine reports could not be retrieved. The remaining eight full-text articles were assessed for eligibility, and all eight RCTs met the inclusion criteria and were included in the qualitative synthesis.

For the preclinical component, 150 animal studies involving female animal models were screened. Studies were excluded if they (1) used disease-specific models (e.g., Alzheimer’s disease, Parkinson’s disease, ischemia, obesity, arsenic exposure, Toxoplasma gondii infection, cancer, or HIV-1), (2) did not implement exercise as an independent intervention, (3) combined exercise with pharmacological, nutritional, or hormonal treatments, or (4) did not use estrogen-deficient or menopausal models (e.g., non-OVX animals). After applying these criteria and reviewing the full texts, five experimental studies using OVX or aged female models and reporting both behavioral and neurobiological outcomes were included. The full identification, screening, and inclusion process for both human and animal studies are illustrated in Fig. 1.

Fig. 1.

Flow diagram for the selection of human RCTs and preclinical animal studies.

Because the included studies were heterogeneous with respect to populations, exercise protocols, cognitive tests, and mechanistic outcomes, no meta-analysis was performed. Instead, we adopted a narrative synthesis approach. Because this review was designed as a narrative synthesis integrating clinical and preclinical evidence rather than a formal systematic review, a formal risk-of-bias or methodological quality assessment was not performed. Human RCTs were organized by exercise modalities (aerobic, resistance, combined, or mind-body) and cognitive domain (global cognition, executive function, memory). Preclinical findings were then used to identify convergent neurobiological pathways, and finally to propose an integrative framework linking specific exercise modalities to cognitive protection in women across the menopausal transition.

RESULTS

1. Clinical evidence in postmenopausal women

1) Effects of exercise on global cognition

Global cognitive function, typically assessed using screening tools such as the Mini-Mental State Examination (MMSE) and the Rowland Universal Dementia Assessment Scale (RUDAS), provides a clinically relevant index of overall cognitive status and dementia risk in peri- and postmenopausal women. Among the eight RCTs included in this review, four reported global cognitive outcomes. These trials mainly examined resistance-based or mind-body regimens and one combined intervention integrating aerobic exercise with dietary modification. Notably, no RCT has yet evaluated the effects of aerobic exercise alone on global cognitive screening measures in this population, representing an important gap in the literature.

Resistance exercise-based and Pilates-based interventions have generally demonstrated beneficial effects on global cognition in postmenopausal women with mild cognitive impairment (MCI), whereas improvements are less evident in cognitively intact women, likely due to ceiling effects of brief screening tools. Farzane & Koushkie Jahromi [24] demonstrated that an eight-week Pilates program incorporating mat-based resistance exercises using elastic bands, magic circles, and dumbbells (three 75-minute sessions per week) significantly increased MMSE scores in postmenopausal women with MCI (within EG, p<.001), with most participants moving into the normal range. The intervention also altered salivary cortisol and dehydroepiandrosterone sulfate (DHEA-S), suggesting adaptive modulation of hypothalamic-pituitary-adrenal (HPA) axis activity that may contribute to cognitive resilience. In contrast, Garcia-Garro et al. [25] found no significant change in MMSE following 12 weeks of moderate-to-low intensity Pilates in cognitively intact postmenopausal women whose baseline scores were already above 27, consistent with a ceiling effect that limits the sensitivity of MMSE to detect subtle improvements in this group.

A more recent trial extended these findings to community-dwelling older postmenopausal women by combining traditional resistance training with power training components. Coelho-Junior et al. [26] implemented a 22-week program delivered twice weekly and observed significant MMSE improvements in both the traditional resistance and resistance-plus-power training groups compared with controls (group×time interaction, p<.05). Interestingly, serum BDNF did not change despite cognitive improvements, suggesting that global cognition benefits may occur without detectable alterations in peripheral BDNF, or that more brain-specific or time-sensitive biomarkers are needed to capture relevant neuroplastic changes.

Evidence from combined exercise and dietary interventions further supports the potential of lifestyle modification to enhance global cognition, while also emphasizing the complexity of underlying mechanisms. In Elsayed et al. [27], postmenopausal women with MCI participated in a 12-week intervention that combined treadmill-based aerobic exercise (three 50-minute sessions per week at 60-70% HRmax) with the Dietary Approaches to Stop Hypertension (DASH) regimen. RUDAS scores improved significantly in both the exercise-plus-diet group (within-group, p<.01) and the diet-only group (within-group, p<.05), with greater improvements in the exercise group (between-group, p<.01). Estradiol, total and free testosterone, and sex hormone-binding globulin levels changed over the intervention period. However, no statistically significant correlations were found between these hormonal alterations and improvements in global cognition, indicating that sex-hormone shifts alone are unlikely to fully explain the cognitive benefits. Key characteristics and global cognitive outcomes of the included randomized trials are summarized in Table 1.

Table 1.

Characteristics and global cognitive outcomes of randomized controlled trials in peri- and postmenopausal women

Taken together, current RCT evidence suggests that structured exercise–particularly resistance-oriented and Pilates-based modalities, with or without dietary modification–may serve as a promising non-pharmacological strategy to preserve or improve global cognitive function in postmenopausal women with emerging cognitive decline. At the same time, these conclusions are constrained by reliance on brief global screening tools prone to ceiling effects, the small number of trials, and limited biomarker assessment. Moreover, the absence of aerobic-only randomized trials reporting global cognition outcomes means that the specific role of aerobic exercise in maintaining overall cognitive status during the menopausal transition remains to be clarified. In the following sections, we therefore focus on domain-specific cognitive outcomes to examine how different types of exercise influence executive function and memory in postmenopausal women.

2) Domain-specific cognitive effects of exercise

Although brief and easy to administer, global cognitive screening measures such as the MMSE and RUDAS have limited sensitivity to subtle cognitive changes and carry a risk of ceiling effects; therefore, their results should be interpreted with caution [28-30]. In addition, these instruments do not provide a detailed assessment of clinically important cognitive subdomains, such as executive function and memory [29,30]. Accordingly, to more precisely characterize the cognitive effects of exercise in peri- and postmenopausal women, the following sections synthesize RCTs that evaluated executive function and memory as primary or secondary outcomes, organized by exercise modality.

(1) Executive function

Executive function (EF)—including attention, working memory, inhibitory control, and cognitive flexibility—is essential for goal-directed behavior and functional independence in daily life [31]. In this review, we synthesized RCTs examining whether exercise interventions protect or enhance executive function in peri- and postmenopausal women. Across trials, interventions included rhythm-based aerobic exercise (lowimpact dance), mind-body exercise (yoga), dance-based training with higher cardiovascular demand combined with protocols incorporating arousal modulation (Zumba plus caffeine), and resistance-based modalities (resistance-based Pilates; resistance training with or without power components). Because executive outcomes were assessed using heterogeneous tasks, findings are synthesized qualitatively.

Moderate-to-low intensity aerobic exercise or mind-body interventions have been associated with improvements in inhibitory control and selective attention in sedentary menopausal women. Yang et al. [32] conducted a 16-week low-impact dance program (3 sessions/week, 60 min/ session) in 28 sedentary postmenopausal women (exercise n=14; control n=14) and assessed executive performance using the Color–Word Stroop Task (CWST). Reaction time under the incongruent condition decreased by approximately 12% in the exercise group, whereas no meaningful change was observed in the control group, while accuracy remained high in both groups, suggesting improved processing efficiency rather than a speed-accuracy trade-off. Similarly, Chattha et al. [33] randomized 108 peri- and postmenopausal women (exercise n=54; control n=54) to an 8-week yoga program (5 sessions/week, 60 min/session) comprising postures, breathing, and meditation versus an active control condition (walking, stretching, and cyclic meditation) and assessed executive-related attention using the Six-Letter Cancellation Test (SLCT). Both groups improved, with greater gains reported in the yoga group (yoga group: 27.43 to 35.31, p<.001; control group: 26.48 to 30.19, p<.001; between-group, p<.001).

In contrast, evidence from higher-cardiovascular-load dance interventions is less consistent. Ben Waer et al. [34] evaluated a 12-week Zumba program (3 sessions/week, 60 min/session, 65–75% HRmax) in 38 sedentary women who were at least four years postmenopausal and assessed visuospatial working memory and response speed using the Corsi Block-Tapping Task (CBTT). Pre-post comparisons indicated no significant changes in CBTT outcomes, despite improvements in physical fitness, with authors noting potential limitations such as fatigue at higher heart-rate load and limited cognitive task demand. Importantly, Ben Waer et al. [35] examined whether augmenting arousal during dance-based training modulates executive outcomes by comparing caffeine+Zumba (CZG), Zumba-only (ZG), and control conditions (CG). In 57 postmenopausal women, participants were allocated to CZG (n=19), ZG (n=19), or CG (n=19), completing a 12-week intervention (3 sessions/week, 60 min/session) at a target heart rate of 140-160 bpm; caffeine supplementation was administered in the combined group. Attention (reaction time) and visuospatial working memory (CBTT) were assessed. Reaction time improved only in the CZG (group×session interaction, p<.05), whereas ZG and CG showed no comparable change, indicating the observed benefits may reflect arousal-related pharmacological effects rather than exercise training per se, thereby limiting inference regarding exercise-specific executive adaptations.

Resistance-based exercise interventions provide complementary evidence for executive function-related benefits, particularly on outcomes reflecting verbal fluency, set-shifting, and cognitive-motor integration. Garcia-Garro et al. [25] examined a 12-week resistance-based Pilates program (2 sessions/week, 60 min/session, moderate intensity) in postmenopausal women randomized to a Pilates group (n=55) or a control group (n=52). The intervention improved performance on the Isaacs Test (group×time interaction, p<.05), Trail Making Test Parts A and B (TMT-A and TMT-B; TMT A group×time interaction, p<.05; TMT B group × time interaction, p<.05), alongside improvements in physical function, supporting the possibility that Pilates may engage executive processes via motor learning, attentional regulation, and coordinated breathing-movement demands. Extending this line of evidence, Coelho-Junior et al. [26] evaluated a 22-week program (2 sessions/week, 60 min/session) comparing resistance training alone versus resistance training plus power training in postmenopausal women. Thirty-six participants were randomized to Traditional Resistance Training (TRT; n=10), Power Training+Resistance Training (PTRT; n=12), or a control group (CG; n=14), and executive-related functional performance was assessed using a dual-task paradigm (Timed Up and Go with the verbal fluency task (Animal Category)). Both the TRT and PTRT groups showed significant improvements in dual-task performance (group×time interaction, p<.05), whereas serum BDNF did not change, suggesting that observed benefits may occur via mechanisms independent of peripheral BDNF. The characteristics and domain-specific outcomes (executive function and memory) of the included trials are summarized in Table 2.

Table 2.

Characteristics and executive and memory-related outcomes of randomized controlled trials in peri- and postmenopausal women

Collectively, available RCTs suggest that executive-function benefits in peri- and postmenopausal women are more consistently observed when interventions combined manageable physiological load with substantive cognitive engagement (e.g., inhibitory control, selective attention, set-shifting, or dual-task requirements). Conversely, higher-load dance interventions and trials incorporating pharmacological co-interventions (e.g., caffeine) yield less straightforward inference regarding exercise-specific executive adaptations. Nonetheless, conclusions remain constrained by modest sample sizes, heterogeneity of EF endpoints, and limited mechanistic testing; future trials should prioritize domain-sensitive executive outcomes and incorporate multi-level biomarkers and/or neuroimaging to clarify modality-specific pathways.

(2) Memory

Memory–particularly episodic and hippocampal-dependent memory–is a cognitive domain that has been reported to be vulnerable during the menopausal transition and in postmenopausal women. Longitudinal cohort studies have shown that midlife women may experience subtle declines in memory performance across the menopause transition, potentially related to changes in ovarian hormone exposure [36]. Experimental and clinical evidence further suggests that estrogen plays a critical role in supporting hippocampal structure and synaptic plasticity, processes that are essential for episodic memory function [37,38]. Given its relevance to later-life cognitive decline and dementia risk, memory represents an important cognitive domain in peri- and postmenopausal women. In the present review, memory-specific outcomes were reported in only two RCTs, and in both cases, memory was assessed alongside executive-function outcomes.

Across the two RCTs that reported memory-specific outcomes in peri- and postmenopausal women, memory was assessed alongside executive function measures, with consistent indication of improvement following both mind-body and resistance-based modalities. In Chattha et al. [33], yoga was associated with greater improvements in overall memory performance as assessed by the Punit-Govil Intelligence Memory Scale (PGIMS) compared to an active control condition. Similarly, Coelho-Junior et al. [26] reported improvements in memory performance measured by a Picture Memory Test following both traditional resistance training and resistance training combined with power components relative to control. Notably, despite these behavioral improvements (group×time interaction, p<.05), serum BDNF did not change [26], suggesting that mechanistic evidence remains limited and that memory-related benefits observed in current trials are not readily explained by peripheral neurotrophic markers. Key characteristics and memory-related outcomes of these trials are also presented in Table 2.

Overall, the current randomized evidence on memory outcomes in peri- and postmenopausal women remains preliminary, as it is based on only two trials employing different memory assessments and evaluating memory as a secondary outcome alongside executive function, which limits generalizability and modality-specific inference. Although both mind-body (yoga) and resistance-based training interventions were associated with improved memory performance, the small number of studies, modest sample size, and limited mechanistic testing constrain inference regarding modality-specific effects and underlying mechanisms. Future trials should therefore incorporate domain-sensitive, standardized memory measures—particularly episodic and hippocampal-dependent outcomes—and include brain-relevant mechanistic assessments (e.g., neuroimaging and multi-marker panels) to clarify whether and how exercise confers memory-specific protection during and after the menopausal transition.

2. Preclinical evidence from OVX animal models

Menopause represents a stage of neuroendocrine aging that may increase vulnerability to cognitive decline [1]. The loss of gonadal sex steroids–particularly 17β-estradiol (E2)–is accompanied by widespread changes in neuronal systems [7] that influence synaptic transmission, neuronal survival, and gene expression through estrogen receptors distributed throughout the brain, specifically in the hippocampus, hypothalamus and cerebral cortex [39-43]. While human exercise trials can quantify behavioral outcomes and, in some cases, peripheral biomarkers, they are inherently limited in their ability to directly interrogate brain-region-specific molecular and cellular processes. Accordingly, this section synthesizes evidence from OVX rodent models as a complementary preclinical evidence stream aimed at elucidating mechanisms of estrogen-deficiency-related neural vulnerability and exercise-responsive neuroprotection. Importantly, the purpose of this synthesis is not to extend clinical efficacy claims from human studies, but to integrate mechanistic insights that are difficult to assess in human cohorts and to inform hypothesis generation for future translational research.

To investigate these processes under controlled experimental conditions, OVX rodents have been widely used as a preclinical model of menopause. OVX is a surgical model of menopause that removes the bilateral ovaries, resulting in undetectable E2 levels within 1–2 weeks. Subsequent estrogen deprivation induces a cascade of neurobiological alterations across brain regions. For example, OVX downregulates BDNF and its receptor tropomyosin receptor kinase B (TrkB), increases oxidative stress, and activates pro-apoptotic proteins such as Bcl-2-associated X protein (Bax) and caspase-3 [44-46]. Functionally, these molecular disturbances manifest as hippocampal atrophy, diminished neurogenesis, and impaired memory performance in behavioral tasks such as the Morris water maze (MWM) and novel object recognition (NOR) tasks.

1) OVX-induced brain impairments

Estrogen deprivation following OVX induces a series of neurobiological disturbances involving oxidative stress, neurotrophic suppression, apoptotic activation, and cerebrovascular dysfunction that collectively contribute to neurodegeneration. One of the most consistent findings across estrogen-deficiency models is neurotrophic suppression via downregulation of the BDNF-TrkB-cAMP response element-binding protein (CREB) signaling axis [44-47].

E2 binds to its nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), forming ligand–receptor complexes that translocate to the nucleus and bind to estrogen-responsive elements (EREs) within the BDNF promoter to induce transcription [48]. These processes lead to the phosphorylation of transcription factors such as CREB, further facilitating BDNF gene expression and synaptic plasticity [49]. Following OVX, E2 loss reduces ERα/β activation, leading to diminished CREB phosphorylation and BDNF transcription in the hippocampus and cortex [45,50]. Experimentally, hippocampal BDNF protein and mRNA levels are significantly decreased in OVX rodents, along with deficits in spatial learning and memory in the MWM [44-46]. Furthermore, both the wild-type OVX and 3xTg-AD OVX models showed reduced phosphorylated CREB, highlighting the importance of E2 in maintaining CREBdriven transcriptional plasticity [47].

In addition, OVX induces oxidative and mitochondrial dysregulation, as reflected by reduced antioxidant capacity in the brain [51]. This redox imbalance increases reactive oxygen species (ROS), which in turn lead to lipid peroxidation and mitochondrial DNA damage. OVX rodents show decreased hippocampal superoxide dismutase (SOD) activity, along with elevated oxidative markers and lipid peroxidation [44]. Excess ROS activates pro-apoptotic cascades [52]. Consequently, estrogen deprivation shifts the homeostatic balance toward pro-apoptotic signaling and diminishes neurogenesis. In the hippocampal dentate gyrus, OVX reduces proliferative (BrdU⁺) and immature neuronal (DCX⁺) cell populations while increasing Bax and cleaved caspase-3 expression and decreasing Bcl-2, resulting in increased apoptosis and neuronal loss [46]. OVX also disrupts neuronal membrane homeostasis and cholinergic transmission. Elevated Na⁺/K⁺-ATPase and AChE activities reflect compensatory adaptation to estrogen–deprivation–induced synaptic inefficiency and cholinergic dysregulation [53].

Functionally, these molecular alterations translate into pronounced behavioral impairments. OVX rodents consistently show prolonged escape latency and reduced target-zone occupancy in the MWM, diminished step-down avoidance latency, and lower retention scores in passive avoidance tasks [44-46,53]. Collectively, these results indicate that loss of estrogen compromises hippocampal BDNF–CREB signaling, reduces antioxidant defenses, and enhances apoptotic susceptibility, culminating in synaptic instability and memory decline.

Given the brain impairments induced by OVX, exercise has been proposed as a non-pharmacological strategy to restore OVX-induced brain dysfunction. To provide an overview of how exercise interventions influence cognitive performance and associated biomarkers in the OVX model, the characteristics and outcomes are summarized in Table 3.

Table 3.

Characteristics and memory-related outcomes of randomized controlled trials in ovariectomized animals

2) Effects of aerobic exercise on OVX-induced deficits

The restorative effect of aerobic exercise on brain function after OVX has been consistently demonstrated across multiple behavioral tests assessing learning, memory, and affective regulation. Spatial learning and reference memory, measured by the MWM, were impaired following OVX but were markedly restored after voluntary running or treadmill training. Rashidy-Pour et al. [45] reported that 14 days of voluntary wheel running shortened escape latency and increased target quadrant occupancy (between, all p<.05), indicating improved spatial learning and memory consolidation disrupted by OVX. Similarly, Ben et al. [54] demonstrated that four weeks of treadmill running normalized prolonged escape latency (between, p<.01) and corrected spatial bias (between, p<.05), suggesting that aerobic exercise restores hippocampal encoding efficiency.

These behavioral improvements were accompanied by elevation of hippocampal BDNF, TrkB, and phosphorylated CREB. A study suggested that BDNF may have a critical role in this effect. Hippocampal blockade of BDNF or TrkB antagonists completely abolishes the cognitive benefits of running, which supports BDNF signaling in exercise-induced memory improvement [55]. Upon BDNF binding, TrkB receptors become phosphorylated and activate downstream signaling that promotes CREB phosphorylation and transcription of genes involved in synaptic plasticity [55,56]. Phosphorylated CREB binds to the Bdnf promoter and initiates BDNF transcription [50]. Newly synthesized BDNF may reinforce TrkB signaling, thereby contributing to synaptic activity, including vesicle mobilization, postsynaptic density, and dendritic spine stability that are required for long-term potentiation and memory consolidation [55,57,58].

Importantly, aerobic exercise has been shown to increase BDNF expression through multiple mechanisms. Muscle contraction induces peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which upregulates fibronectin type III domain-containing protein 5 (FNDC5) and promotes irisin secretion. Irisin may cross the blood-brain barrier and stimulate neuronal Bdnf transcription [59,60]. Simultaneously, aerobic exercise elevates circulating insulin-like growth factor-1 (IGF-1) and further enhances CREB phosphorylation and Bdnf transcription in the hippocampus [61,62].

Recognition memory and affective regulation were assessed using the NOR and EPM tests. In Rocha-Gomes et al. [44], eight weeks of high-intensity interval training (HIIT) improved discrimination indices in the NOR (S×T interaction, p<.05) and time spent in center zone (S×T interaction, p<.05), indicating enhanced recognition memory and reduced anxiety-like behavior. These behavioral improvements coincided with elevated hippocampal BDNF and SOD (S×T interaction, p<.05), suggesting improved neuronal function and antioxidant capacity [44]. Under oxidative stress, excess ROS impair CREB signaling and suppress Bdnf expression [63,64]. Therefore, exercise-induced upregulation of SOD may restore redox balance and BDNF transcription.

Exploratory and anxiety-related behaviors were evaluated in the Dark-Light Box and Boissier’s Four-Hole Board tests in García-Mesa et al. [47]. OVX animals exhibited reduced exploration and worsened anxiety, both reversed by 3 months of voluntary exercise (O×E interaction, p=.014, and between, p=.02) [47]. Exercise elevated hippocampal BDNF (between, p=.001) and catalase RNA (between, p<.05) [47]. Upregulated catalase RNA may promote neuronal energy efficiency and contribute to Bdnf expression through FNDC5 and irisin signaling from skeletal muscle to the brain [59].

Collectively, evidence from voluntary running, treadmill, and HIIT suggests that aerobic exercise ameliorates OVX-induced impairments in spatial learning (MWM), recognition memory (NOR), and affective behavior (EPM, Dark–Light, Four-Hole Board). These behavioral recoveries may be supported by interlinked cellular programs that include BDNF–TrkB–CREB-dependent synaptic remodeling, and catalase antioxidant defense. These findings collectively suggest that exercise can reestablish neuronal plasticity, metabolic competence, and cognitive–affective stability compromised by estrogen deficiency.

3) Effects of combined exercise on OVX-induced deficits

Combined aerobic and resistance exercise was associated with a neuroprotective effect on neurotrophin signaling, neuronal survival, and neurogenesis. In OVX rats, Kim et al. [46] showed that a combined exercise program composed of treadmill running and tower-climbing resistance training was performed 6 days per week (3 days aerobic, 3 days resistance) for eight weeks. Cognitive performance was evaluated using the Step-Down Avoidance Task (SDAT) for short-term aversive memory and the MWM for spatial learning and reference memory [46]. OVX animals exhibited prolonged latency and reduced target-quadrant occupancy, indicative of impaired learning and memory [46]. However, combined training restored both parameters to control levels (all between, p=.017 and p=.006), demonstrating recovery of hippocampal-dependent cognitive function [46].

In addition, combined exercise enhanced hippocampal neurogenesis, as evidenced by increased numbers of BrdU⁺ proliferative cells (between, p=.004) and DCX⁺ immature neurons in the dentate gyrus (between, p<.001) [46]. This was accompanied by reduced pro-apoptotic signaling (between, p<.05) and increased Bcl-2 expression (between, p<.05), which supports enhanced neuronal survival [46]. The upregulation of BDNF and TrkB suggests that neurotrophin signaling may be involved in the observed effects on neurogenesis and survival [46].

Exercise-induced activation of BDNF-TrkB signaling leads to CREB phosphorylation [65]. CREB then promotes transcription of genes involved in neuronal survival and neurogenesis, including Bcl-2, and reduces pro-apoptotic signaling such as Bax and caspase-3 activation [65,66]. In parallel, resistance exercise increases hippocampal IGF-1 signaling, which complements BDNF–TrkB signaling to promote neuronal growth and dendritic remodeling [67,68]. Fig. 2 summarizes the effects of exercise associated with partial recovery of OVX-induced brain dysfunction.

Fig. 2.

Molecular mechanisms of OVX-induced brain dysfunction and the effects of aerobic and combined exercise in animal models. OVX induces brain dysfunction by reducing BDNF expression and neurogenesis while increasing ROS and apoptotic signaling. Aerobic exercise restores brain function primarily through BDNF-related pathways involving PGC-1α, IGF-1, and antioxidant capacity, whereas combined exercise further enhances hippocampal neurogenesis, neuronal and dendritic growth, and reduces apoptosis.

DISCUSSION

Exercise-related cognitive outcomes in peri- and postmenopausal women appear to be domain-sensitive rather than uniform, with more consistent signals observed for specific cognitive domains than for global screening outcomes [24-27]. In many trials, global cognition is assessed using brief screening instruments such as the MMSE and RUDAS, which are practical but may exhibit limited sensitivity and ceiling effects, thereby reducing the likelihood of detecting modest changes in cognitively intact populations [28-30]. Consistent with this measurement constraint, exercise interventions characterized by low-to-moderate intensity and sustained cognitive engagement (e.g., coordination, learning demands, or dual-task elements) tend to show more reproducible improvements in executive function [25,26,32-34]. In contrast, trials that incorporate complex co-interventions or potential confounders (e.g., adjunctive caffeine or multi-component programs without factorial separation) can limit causal attribution to exercise alone [27,35]. Evidence for memory remains preliminary, given the small number of RCTs (n=2) and the heterogeneity of memory assessment; nevertheless, mind–body and resistance-based exercise interventions have shown favorable trends in some studies [26,33]. Overall, these findings suggest that the interaction between exercise intensity and cognitive engagement may be a key determinant of executive function outcomes, while more sensitive and harmonized memory endpoints are needed to strengthen inference.

Preclinical OVX models provide mechanistic plausibility for these domain-level patterns while underscoring important translational limits. OVX induces convergent neurobiological disturbances, including suppression of the BDNF–TrkB–CREB axis, oxidative/mitochondrial dysregulation with reduced antioxidant capacity, and activation of pro-apoptotic cascades; functionally, these alterations manifest as hippocampal atrophy, diminished neurogenesis, and impaired memory performance in hippocampus-dependent tasks (e.g., MWM and NOR) [44-47,54]. Across studies that assessed neurotrophic pathways, exercise-related recovery of memory performance was generally accompanied by restoration of BDNF-linked plasticity and CREB-related transcription; however, this convergence should be interpreted as “where assessed,” because biomarker panels and sampling approaches varied across aerobic paradigms [44,47,64]. Evidence consistent with cell-survival and neurogenesis-related mechanisms emerges most clearly in combined aerobic-plus-resistance paradigms, in which behavioral recovery co-occurred with coordinated shifts away from apoptosis (e.g., reduced Bax and cleaved caspase-3 with increased Bcl-2) and increases in neurogenesis indices (e.g., BrdU and DCX) [46]. Nevertheless, preclinical tasks predominantly probe hippocampal-dependent memory (e.g., spatial navigation), limiting direct mapping to executive function outcomes in human trials. This mismatch largely reflects the structure of the currently available literature rather than an interpretive weakness of the present review. In the limited human RCT literature, global cognition and executive function were assessed more frequently than hippocampal-dependent memory, whereas preclinical OVX models are better suited to the mechanistic investigation of hippocampal plasticity than to direct evaluation of constructs equivalent to global cognition or executive function in human trials. Moreover, because many OVX paradigms are aerobic-centered, translation to the diverse modalities implemented in peri- and postmenopausal RCTs remains incomplete. Collectively, the preclinical literature supports a convergent but incomplete mechanistic model in which aerobic exercise preferentially engages neurotrophic and redox pathways, whereas combined training may extend mechanistic coverage toward cell-survival processes that are difficult to verify directly in clinical trials [44-47,54,59-69].

The present study has several limitations, including a small number of eligible human and preclinical studies, substantial heterogeneity in participant characteristics, intervention protocols, outcome measures, and biomarker assessments, all of which make the findings difficult to generalize and limit mechanistic interpretation. Because a formal risk-of-bias or methodological quality assessment was not performed, the certainty of the synthesized conclusions should be interpreted with caution. In addition, the effects of exercise by menopausal stage could not be clarified because seven of the eight included studies involved postmenopausal women, whereas only one involved perimenopausal women, making meaningful stage-specific comparison difficult. Subtle changes may also have been missed because global cognitive screening tools are susceptible to ceiling effects, while evidence for memory remains preliminary because only two studies assessed this domain using different measures. Finally, although preclinical studies suggest plausible mechanisms, their findings cannot be directly translated into clinical effects because of differences in exercise modalities and evaluation methods between animal and human studies. These preclinical findings should therefore be interpreted as providing biological plausibility and hypothesis-generating support for clinical observations, rather than as a direct basis for evidence-based exercise recommendations in peri- and postmenopausal women.

Future RCTs should adopt more domain-specific and methodologically rigorous designs to improve causal interpretability and clinical relevance. First, trials should standardize domain-sensitive cognitive batteries that prioritize executive control (e.g., Stroop interference, TMT-A/B, dual-task paradigms) and hippocampal-dependent memory, rather than relying primarily on global screening tools [25,26,28-30,32]. Second, participant stratification and/or analytic modeling should incorporate key moderators—menopausal stage, baseline cognitive status, cardiometabolic risk, and adherence/tolerability—to reduce heterogeneity and clarify for whom and under what conditions exercise is most protective [24-27,32-36]. Third, mechanistic profiling should be harmonized and hypothesis-driven, integrating sex-steroid hormones and stress-related markers (e.g., cortisol, DHEA) alongside biomarkers aligned with OVX-informed pathways (neurotrophic signaling and redox/mitochondrial defenses), with careful attention to sampling timing and analytic consistency [24,27,44-47,54,59-64]. Finally, because adjuncts and multi-component interventions can obscure exercise-specific effects, designs that isolate exercise (exercise-only arms) or formally test adjuncts using factorial approaches are warranted to improve attribution and mechanistic inference [27,35]. Collectively, integrating domain-specific outcomes, mechanism-aligned biomarkers, and practical exercise prescriptions that combine feasible physiological loading with meaningful cognitive engagement will strengthen the evidence base for exercise as a cognitive-protection strategy across the menopausal transition [24-27,32-35,44-47].

CONCLUSION

Exercise may support cognitive health in peri- and postmenopausal women; however, the evidence remains heterogeneous across studies. Human RCTs suggest domain-sensitive cognitive signals—most consistently in executive outcomes—whereas effects on brief global screening measures and memory are harder to detect and/or preliminary, partly due to limited sensitivity and variability in assessment methods. These clinical patterns are biologically plausible in light of preclinical OVX evidence implicating neuroplasticity- and redox-related pathways (e.g., BDNF-CREB and oxidative/mitochondrial regulation). Preclinical evidence may help explain the biological plausibility of these patterns, but it should be interpreted as supportive and hypothesis-generating rather than as a direct basis for clinical exercise prescription. Future trials should prioritize domain-sensitive cognitive batteries, mechanism-aligned biomarkers, and designs that improve causal attribution by clarifying the respective contributions of cognitive engagement and exercise intensity and by isolating exercise effects when adjuncts are tested.

Article information Continued