Authors: Mun Sun Choi, Emily R. Seiger, Laura E. Murray-Kolb
Categories: Review, iron, iron deficiency (ID), iron deficiency anemia (IDA), perimenopause, menopause transition (MT), perimenopausal menorrhagia (PM), abnormal uterine bleeding (AUB), postmenopause, midlife, women’s health, cognitive function
Source: Nutrients
Doi: 10.3390/nu17111762
Authors: Mun Sun Choi, Emily R. Seiger, Laura E. Murray-Kolb
Menopause is associated with significant hormonal and reproductive changes in women. Evidence documents interindividual differences in the signs and symptoms associated with menopause, including cognitive decline. Hypothesized reasons for the cognitive decline include changes in hormone levels, especially estrogen, but study findings have been inconsistent. Hormone replacement therapies (HRTs) are often recommended to alleviate menopause-related symptoms in both peri- and postmenopausal women. However, the North American Menopause Society does not recommend the use of HRT for the management of cognitive complaints in perimenopausal women due to lack of evidence. Additionally, there are many women for which the use of HRT is contraindicated. As such, it would be helpful to have an alternative method for alleviating symptoms, including declines in cognition, during the menopause transition. Iron supplementation may be a promising candidate as it has been associated with improved cognitive performance in premenopausal women with iron deficiency and iron deficiency anemia. Because many women will experience heavy blood losses during perimenopause, they are at risk of becoming iron deficient and/or anemic. The use of iron supplementation in women with iron deficiency may serve to not only improve iron status but also to alleviate many of the signs and symptoms associated with perimenopause (lethargy, depressed affect, etc.), including cognitive decline. However, evidence to inform treatment protocols is lacking. Well-designed studies of iron supplementation in perimenopausal women are needed in order to understand the potential of such supplementation to alleviate the cognitive decline associated with perimenopause.
According to the World Health Organization (WHO), the number of individuals over the age of 60 exceeded the number of children younger than the age of 5 in 2020. In anticipation of many countries continuing to observe a shift in the population age structure towards older ages, definitions of healthy aging were formalized when the WHO developed the Global Strategy and Action Plan on Aging and Health for 2016–2020 [1]. Following its release, the number of new scientific publications listed in PubMed related to healthy aging increased exponentially, peaking in 2021 when more than 5300 healthy aging articles were published. While definitions of healthy aging vary by field, the Global Strategy and Action Plan on Aging and Health for 2016–2020 defines healthy aging as the “process of developing and maintaining the functional ability that enables well-being in older age” with the emphasis on acknowledging diversity in the trajectory and process of aging and reducing inequity.
In order to maintain functional ability with aging, the WHO stresses the importance of maintaining interactions between intrinsic capacity, the combination of an individual’s physical and mental capacity, and environmental characteristics, such as social networks and services provided by communities [2]. In aging women, menopause, the point marking the end of women’s reproductive years, may play a role in disrupting these interactions [3]. Menopause is clinically defined as amenorrhea, or absence of menstrual bleeding, lasting for at least 12 months. It is a normal physiological process due to loss of ovarian follicular function and decline in estrogen levels [4]. As women reach menopause, they are affected by varying degrees of physical, mental, and/or emotional changes [5]. There are many signs and symptoms that are associated with menopause, including vasomotor (i.e., hot flashes, night sweats, insomnia), genitourinary (i.e., abnormal uterine bleeding, vaginal dryness), cardiovascular (i.e., hypertension), and psychogenic symptoms (i.e., anxiety, depression), which may persist and/or worsen throughout menopause and postmenopause [6].
It is estimated that approximately 47 million women become menopausal each year, and the world population of menopausal and postmenopausal women will increase to 1.2 billion by 2030 [7]. In addition, women in high-income countries with access to advanced medical care are expected to live approximately 40% of their lives postmenopausal [8]. Signs and symptoms associated with menopause are shown to have a significant impact on work outcomes, and it is estimated that USD 1.8 billion is lost annually in the United States (US) based on missed workdays related to menopause [9]. Despite its prominent impact on a large portion of the world population as well as much of the world’s economy, less than one percent of pre-clinical trials related to the biology of aging include the modeling of menopausal phenotypes observed in humans, with even fewer focusing on perimenopause [3].
Perimenopause refers to the menopause transition—the time of menstrual irregularity and significant hormonal and reproductive changes leading up to the beginning of menopause [10,11]. Perimenopause typically begins in the fifth decade of life, but there are differences in the onset, duration, and severity of signs and symptoms, with many of the symptoms remaining ill-defined. Thus, the diagnosis is made retrospectively, based on the patient’s age and complaints of signs and symptoms, which contributes to most women facing these physical, emotional, and cognitive changes unprepared [6]. Yet, menopause is an inevitable phase in women’s lives that has strong potential to influence quality of life (QOL) and family dynamics [12].
Cognition is an umbrella term that encompasses various aspects of intellectual functions and processes, including attention, memory, decision-making, planning, comprehension, and reasoning [13]. Cognitive decline is often observed with aging and considered part of normal physiology [14]. In addition, various factors including hormonal fluctuations may exert a great influence on women’s brain functions as they go through different stages of menopause, leading to varying degrees of depressive symptoms, insomnia, and cognitive dysfunction [15,16,17,18]. Thus, the early management of subjective cognitive decline is recommended to maintain QOL and to mitigate the risks of neurodegenerative diseases, especially Alzheimer’s disease, in later life [19,20].
The WHO has identified iron deficiency (ID) as a major public health concern due to its high prevalence, especially in women [21]. If left untreated, ID can lead to anemia. The worldwide prevalence of anemia in women over the age of 60 is approximately 14%, with iron deficiency anemia (IDA) being the most common etiology [22]. Iron plays a crucial role in brain function through oxygen transportation, myelination, neurotransmitter synthesis and regulation, synaptogenesis, and energy expenditure [23,24,25,26]. Thus, the maintenance of a normal physiological brain function requires proper iron homeostasis. Aging is shown to cause disruptions in iron homeostasis as well as redistribution of iron within the brain due to inflammation and changes in the permeability of the blood–brain barrier, which may lead to neuroinflammation and neurodegeneration [24,27,28,29].
One of the many adverse outcomes associated with ID and IDA in adults is diminished cognitive function [30,31]. In young women of reproductive age, ID and IDA negatively affect attention, memory, learning, and behavior [23,32,33,34], and several intervention studies have shown improved cognitive function in those supplemented with iron, suggesting the reversibility of cognitive changes associated with ID and IDA in adulthood. Even in the absence of anemia, ID is associated with a significant decline in cognitive function in geriatric patients [35]. However, studies have not elucidated which specific aspects of cognitive function are affected by ID in the older population, nor have they examined whether iron supplementation is effective at improving cognitive function in this population.
One of the menstrual irregularities that can occur during the menopausal period is perimenopausal menorrhagia (PM). PM, or perimenopausal abnormal uterine bleeding, is defined as abnormally heavy bleeding during the menopause transition. Such heavy bleeding can place a woman at risk of the development or worsening of ID and IDA. PM is estimated to affect at least 25% of perimenopausal women and, in the US, it is estimated that more than 90% of women will experience at least one episode of PM and 78% of those will experience at least three episodes. In addition, abnormal uterine bleeding accounts for 14% of all US hospitalizations among women aged 45–54 years [36]. Women experiencing PM frequently complain of fatigue and impaired work performance, mimicking complaints raised by women with ID and IDA [37,38]. Despite this knowledge, the prevalence of ID and IDA in perimenopausal women and their functional consequences have received little attention.
Based on the high prevalence of PM and existing evidence regarding the association between iron status and cognitive function, assessing and managing women’s iron statuses may be a relatively simple and cost-effective way to mitigate cognitive decline in perimenopausal women. However, before specific recommendations can be made, intervention studies are needed in this population to better understand the relationship between women’s cognitive functions and iron statuses during perimenopause. The purpose of this article is to review the current evidence regarding the impact of different menopausal stages on women’s iron statuses and cognitive functions in order to uncover knowledge gaps where more evidence is needed so that interventions to appropriately manage the problems associated with ID/IDA in perimenopausal women can be developed.
For the purpose of this narrative review, a literature search was conducted in PubMed, Embase, MEDLINE, Scopus, Web of Science, and CINAHL, where the search terms used include iron, perimenopausal menorrhagia, abnormal uterine bleeding, perimenopause, postmenopause, menopause, cognition, learning, executive function, attention, verbal, and memory. Inclusion criteria were articles investigating healthy human subjects who are classified as late pre-, peri-, and postmenopausal and not using hormone replacement therapy (HRT). A total of 1363 studies were initially identified, but 351 were duplicates. Thus, 1012 studies were screened. During screening, 611 studies were identified to be irrelevant due to the (1) inclusion of patients with chronic illness such as cancer, renal disease, and heart disease, (2) research question, intervention, and/or outcome not relevant for the scope of this review, (3) inclusion of patients with cognitive dysfunction and/or mental disorders such as schizophrenia and autism, (4) no objective measurement of cognitive function, (5) no or unclear inclusion of peri- and/or postmenopausal women, (6) use of psychoactive drugs as the intervention and/or inclusion of psychoactive drug users, (7) article type/study design not relevant, (8) use of HRT as the intervention, (9) use of animal models, (10) inclusion of women undergoing/who underwent surgical menopause, and (11) published in a language other than English. Within 401 studies that were assessed for eligibility, 357 were excluded due to there being (1) no measurement of a relevant outcome of interest, (2) intervention not aligned with the review question such as the use of HRT, (3) article type/study design not relevant, (4) use of animal models, (5) inclusion of HRT users, (6) no clear differentiation of menopause stages, (7) inclusion of women with surgically induced menopause, (8) inclusion of men within analyses, (9) inclusion of women with metabolic syndrome and/or chronic disease, (10) full text not available, (11) published in a language other than English, (12) article retracted, and (13) inclusion of women on psychoactive drugs. In total, 44 studies are discussed in this review article (Figure 1).
Menopause not only marks a reproductive transitional stage but also a neurological transitional stage, which is associated with symptoms such as insomnia, mood changes, and cognitive decline [19,39,40]. Approximately 44–62% of women experience subjective cognitive decline during the menopause transition, often persisting into postmenopause [41,42,43]. Perimenopausal women have an option to receive HRT to manage signs and symptoms related to the beginning of menopause. Limited evidence suggests that early initiation and continued use of HRT after perimenopause may be associated with better verbal recognition and enhanced hippocampal function later in life [44]. However, the North American Menopause Society does not recommend the use of HRT during perimenopause for the purpose of managing cognitive complaints due to the lack of evidence [45]. In addition, the effectiveness of HRT is not guaranteed, and it may be contraindicated due to a family or medical history such as cardiovascular disease [46,47]. Therefore, identifying other possible interventions, such as iron supplementation, for perimenopausal women who are experiencing cognitive changes could be useful. Given the link between iron status and cognitive function in premenopausal women, iron supplements may be a prospective treatment to alleviate cognitive decline in perimenopausal women [23,30,31,32] but current evidence to support this is sparse, especially in those with PM [48].
Valentina et al. [49] investigated the relationship between ferritin concentrations and cognition (composite score of episodic memory, phonemic/semantic fluency, working memory, and mental flexibility) in perimenopausal women. Surprisingly, the authors found some support for a role of lower ferritin concentrations in overall better cognitive performance; however, these results should be interpreted with caution (Table 1) [49]. First, iron status was assessed only at the beginning of the study while cognitive performance was assessed only at follow-up, which was 13 years later. Thus, there was no control for concurrent iron status when cognitive performance was assessed. Due to iron status changing throughout the life course depending on food and/or supplement intake, changes in absorption, and other physiological changes, it is difficult to definitively link ferritin status from 13 years prior to the measured cognitive performance. Second, ferritin is a well-known acute-phase protein, but no markers of inflammation were measured in the study. Therefore, the association between ferritin and cognition may have been confounded by inflammation.
On the other hand, a recent study by Barnett et al. investigated the relationship between cognitive performance and systemic and brain iron levels in menopausal women with iron sufficiency and ID without anemia. A higher serum ferritin percentile was associated with higher accuracy, higher discriminability, and shorter reaction times in all cognitive tasks assessed (Table 1). In addition, higher values of iron biomarkers that are associated with oxygen transport such as hemoglobin, red blood cell count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were related to a better performance in cognitive tasks. The positive relationship between cognitive performance and systemic iron levels observed in menopausal women in the study by Barnett et al. highlights the clinical significance of iron and need for additional studies to confirm these findings, especially in perimenopausal women [50]. Specifically, studies that are adequately powered and, preferably, randomized controlled trials investigating the impact of iron supplementation on iron status and cognitive function in perimenopausal women with ID and IDA are needed.
Postmenopausal women’s iron statuses typically improve over time as iron is no longer lost through menstruation [51]. Additionally, during menopause, an inverse relation between decreasing estrogen and increasing iron levels, specifically serum ferritin concentrations, has been reported [52,53,54]. While there are reasonable concerns regarding a link between increased iron storage in postmenopausal women and an increased risk of cardiometabolic diseases, cancer, and neurodegenerative disorders, the prevalence of elevated iron stores in postmenopausal women is low [53,55,56]. On the other hand, the prescription of HRT, which is associated with lower iron stores in women, is steadily increasing [46,56]. Additionally, postmenopausal bleeding, which accounts for two-thirds of all gynecologic office visits in postmenopausal women, and increased malabsorption of iron as women age also contribute to IDA in postmenopausal women [57,58]. Thus, while the absence of menstruation is typically accompanied by an improvement in iron status in postmenopausal women, not all postmenopausal women are protected from ID and/or IDA and, therefore, may still be susceptible to the adverse cognitive effects of ID [59]. However, as stated above, specifics regarding cognitive effects of ID in postmenopausal women remain unknown, due to an insufficient number of research studies investigating this association.
In particular, there is a lack of direct evidence linking cognitive function and iron status in peri- and postmenopausal women. Emerging evidence [50] suggests that changes in cognitive function observed in perimenopausal women with ID appear to mimic changes in cognitive function in premenopausal women with ID and IDA [23,32,33,34]. In order to adequately examine iron supplementation as a plausible solution to mitigate cognitive decline in perimenopausal women with ID and IDA in future studies, the impacts of menopause stages, menopausal signs and symptoms, and the duration of reproductive life on cognitive function in peri- and postmenopausal women are further explored in this review.
A significant decline of estrogen during menopause has been associated with lower cognitive performance in mid- and later life [60,61,62]. Estrogen is responsible for the modulation of neurogenesis and synaptic plasticity and cognitive processing, as shown in functional magnetic resonance imaging (fMRI) [63]. Thus, a decline in estrogen concentration, especially in the brain, affects neural processes through genomic and non-genomic actions that influence the neuronal number, gene expression, and glucose metabolism [19,64]. In addition, estrogen receptors are widely distributed in various regions of the brain, and changes in the concentration of estrogen in the brain may trigger dysregulation of estrogen signaling, leading to changes in neurological function [19,65,66].
A significant portion of perimenopausal women experience cognitive decline [18]. Cognitive domains that appear to be most affected during perimenopause include working memory, attention, processing speed, and verbal memory [67,68,69,70]. These cognitive changes may be associated with hormonal fluctuations and menopausal signs and symptoms such as insomnia, stress, and pain, ultimately affecting perimenopausal women’s QOL [71,72]. Along with other conditions that emerge during perimenopause such as depression and hot flashes, cognitive decline is associated with an increased risk of neurodegenerative diseases in the future if not intervened with [19,20]. Thus, the management of cognitive function is crucial during this stage of menopause.
The impact of perimenopause on cognitive function has been relatively well investigated, but studies regarding the specific domains affected have yielded mixed results. In longitudinal studies conducted by Maki et al., Greendale et al., and Fuh et al., where different domains of cognition were assessed (Table 2), perimenopausal women demonstrated varying degrees of cognitive decline, specifically in learning [67], verbal fluency [69], verbal memory [68], processing speed [68], and attention/working memory [67]. However, Meyer et al. reported that women in the premenopausal and early perimenopausal phases had improved working memory and perceptual speed performance at yearly follow-ups, compared to their first assessment [73]. Cross-sectional studies by Chalise et al., Chen et al., Coslov et al., and Mathew et al. reported that perimenopausal women experienced more frequent and/or severe symptoms associated with poor memory and brain fog than pre- and postmenopausal women [70,74,75,76]. In contrast, Zhang et al. reported that postmenopausal women experienced more severe and frequent “cognitive symptoms”, specifically hypomnesia and lack of concentration, than perimenopausal women in China [77] (Table 2).
Neuroimaging technologies have also been utilized to investigate the association between perimenopause and women’s cognitive performance [78,79,80]. Zhang et al. and He et al. used resting-state fMRI and calculated regional homogeneity values, which reflect the synchronization of neuronal activity in the local brain region [78,80,81]. Both studies found that perimenopausal women had altered patterns of regional homogeneity compared to pre- [78] and postmenopausal women [80], which may be correlated with clinical measures of cognitive function (Table 2) [78]. However, these results should be interpreted with caution as these brain activities were not measured during cognitive task performance. In addition, He et al. compared the cognitive performance of perimenopausal women to that of premenopausal women [78], while Zhang et al. compared the cognitive performance of perimenopausal women to that of postmenopausal women [80]. Lastly, a cross-sectional study reported that perimenopausal women had significantly smaller subcortical volumes in the left and right amygdala compared to premenopausal women, and such structural changes in the bilateral amygdala were related to lower working memory accuracy and a longer executive reaction time. However, the study was conducted using magnetic resonance imaging scans, which may not necessarily reflect what fMRI scans may portray [79]. In order to fully understand the degree of change in cognitive performance observed during perimenopause, it is imperative to compare cognitive performance during pre-, peri-, and postmenopause, ideally within one study, and such studies are largely lacking.
Out of many cognitive domains, evidence suggests that working memory, verbal learning, verbal memory, phonemic verbal fluency, attention, and motor function may be more affected in postmenopausal women than pre- and perimenopausal women [43,82,83]. However, results regarding the association between hormones and changes in these cognitive domains in postmenopausal women are not consistent. Berent-Spillson et al. and Weber et al. found that postmenopausal women performed worse in verbal tasks than women in other stages of menopause [43,82]. Ryan et al. found that higher total and free estradiol levels and a higher ratio of testosterone to estradiol were associated with better semantic memory in postmenopausal women. In addition, Ryan et al. found that lower total testosterone and a lower ratio of testosterone to estradiol were associated with better verbal episodic memory in postmenopausal women [84]. In contrast, Epperson et al., Luetters et al., and Herlitz et al. found no associations between endocrine measures and cognitive function across menopause stages [85,86,87] (Table 3).
Lastly, evidence suggests that structural variability in the brain throughout menopause may explain changes in cognitive performance in postmenopausal women. A recent study by Lissaman et al. reported that advanced age in postmenopausal women was associated with lower spatial context memory and microstructural variability in frontal white matter [88]. Jacobs et al. [89] reported a strong correlation between working memory performance and dorsolateral prefrontal cortex–hippocampus connectivity in postmenopausal women, similar to results published by the same group as well as Zhang et al. [90,91]. Later, Seitz et al. found that postmenopausal women showed a positive correlation between regional volumes of anterior cingulate cortex and regional volumes of dorsolateral prefrontal cortex, hippocampus, and inferior parietal cortex, which are regions associated with memory circuitry [92]. A loss of the ability to decrease the resting-state connectivity of left–right hippocampus during the verbal encoding task in postmenopausal women was reported in a recent study, suggesting that altered resting-state functional connectivity in the default mode network may explain changes in memory performances during postmenopause [93] (Table 3).
A substantial body of literature suggests that objective cognitive decline observed in peri- and postmenopausal women may be associated with menopausal signs and symptoms affecting QOL. The importance of monitoring these variables is demonstrated by the cross-sectional and longitudinal studies listed in Table 4. Overall, menopausal signs and symptoms affect cognitive function in peri- and/or postmenopausal women, but studies are yielding inconsistent results regarding their degree of impact.
Sleep disturbances, stress, anxiety, depression, mood symptoms, and vasomotor symptoms were frequently evaluated to assess their impact on cognitive function in peri- and/or postmenopausal women. The severity of insomnia and sleep disturbances was negatively correlated with cognitive function in peri- [94,95,96,97] and postmenopausal women [95,98]. Memory was especially influenced by stress, measured using the serum cortisol concentration or subjective measures of psychosomatic symptoms, in peri- [99] and postmenopausal [99,100] women. Both subjective and objective measures of anxiety, depression, and mood symptoms were associated with poor cognitive function in peri- [94,101] and postmenopausal [100] women [72,102]. Vasomotor symptoms such as hot flashes influenced cognitive function in peri- [94,96] and postmenopausal [100] women [102]. Lastly, QOL [103] and subjective cognitive complaints [104,105,106] were associated with cognitive function, but the population affected by those factors is unclear due to inconsistent results (Table 4). Future studies should appropriately measure and methodologically report the severity of menopausal signs and symptoms to optimally investigate the correlation between cognitive functions in all stages of menopause.
Lastly, evidence suggests that longer lifetime exposure to estrogen from a longer reproductive life and older age at menopause may attenuate the severity of cognitive decline in women during menopause (Table 5). Overall, better cognitive function in postmenopausal women is associated with a younger age at menarche [107], later age at natural menopause [108], and longer duration of reproductive years [109], but more studies are needed to confirm these findings due to inconsistent results [110]. In addition, the impact of reproductive history on cognitive function in perimenopausal women should be investigated.
Our understanding of the degree of change in cognitive performance observed throughout menopausal stages is hampered by methodological limitations in the studies that have been conducted thus far. Future studies may benefit from several considerations. First, the method used to classify the menopausal stage must be consistent across studies, preferably applying uniform criteria. Currently, the recommended gold standard is the application of the Stages of Reproductive Aging Workshop (STRAW)+10 criteria, which were developed as a more comprehensive basis for the assessment of reproductive aging than the original STRAW criteria published in 2001 [11]. Of the 44 reviewed studies, 17 studies used the STRAW+10 criteria, and 4 studies used the STRAW criteria to classify the menopausal stage. In contrast, 3 studies did not specify the criteria used to classify the menopausal stage and 9 studies depended on self-reported menstrual bleeding patterns/history. While bleeding patterns are relevant, there is no gold standard for individuals or clinicians to accurately report menstrual bleeding patterns/history in a way that is comparable across studies. In addition, recall bias is inevitable when utilizing self-reported data only to determine menstrual bleeding patterns/history. Due to challenges with measuring the exact volume of blood loss and accurately reporting the timing of changes in bleeding patterns, future studies must determine better methods to measure and report menstrual bleeding patterns and utilize the STRAW+10 criteria.
Second, future studies must consider utilizing different approaches to measure cognitive function in this population, especially to confirm subjective experiences of changes in cognitive function and affect. Of 44 studies, 3 studies utilized interviews or study-specific surveys only to test their hypotheses. While qualitative data from interviews and study-specific surveys provide valuable insights, there is a need to further refine and confirm those findings by triangulating evidence with different approaches [111]. For instance, future studies may consider supplementing qualitative data with data obtained via validated questionnaires conducted by clinicians and/or researchers and/or computerized cognitive tasks.
Third, it is possible that the discrepancies observed in different studies may be partly explained by the heterogenous nature of menopause itself. Certain changes in the central neuroendocrine system and ovaries are specific to each stage of menopause, which may explain why different cognitive domains are affected in different stages of menopause [43,83,112]. Evidence suggests that trajectories of estradiol and FSH vary across pre-, peri-, and postmenopausal women, which may partially explain the varying degrees of signs and symptoms observed in postmenopausal women [16]. Yet, it is unclear how changes in cognitive function and affect may interact with the heterogenous nature of menopause itself. Thus, longitudinal studies identifying the degree of biological heterogeneity throughout the course of menopause would help to build a strong foundation for future studies investigating their impact on women’s cognitive function during such a critical period. Lastly, relations between hormone levels and cognitive outcomes were assessed using different sets of hormones and cognitive tests across different studies, which introduces a challenge when trying to interpret and compare results. Also, in addition to hormones affecting changes in cognitive function in menopausal women, there is a need to identify other contributing factors of cognitive decline in this population.
Current evidence indicates that the peri- and postmenopausal stages are accompanied by changes in women’s cognitive function. Due in part to the disparate experiences of menopausal signs and symptoms influenced by hormonal fluctuation, women during the menopausal stages are at risk of cognitive decline. For perimenopausal women with heavy bleeding, the risk of cognitive decline may be exacerbated with heavy blood loss due to ID/IDA, but more studies are needed to understand the role of iron status in cognitive decline for menopausal women. Evidence suggests that ID is related to cognitive changes in young women and that iron supplementation can reverse these cognitive changes. Whether or not iron supplementation during the peri- and postmenopausal stages can alleviate the cognitive decline experienced at these timepoints is a question that has yet to be answered, especially in those with ID. To ensure that future studies are optimally informative, it will be critical for investigators to appropriately measure and methodologically report sociodemographic variables and to choose and interpret cognitive tests appropriately for the target population.
Because cognitive decline during menopause has been understudied, the published literature lacks detailed descriptions of the diverse cognitive experiences of people undergoing menopause. Future studies should consider a multitude of factors that could contribute to cognitive decline during the menopause transition. Factors such as lower educational attainment, untreated mental health disorders, high trauma exposure, substance use, lack of access to healthcare, infectious diseases [113], and adverse childhood experiences [114] contribute to cognitive decline, and women with these experiences may be disproportionately affected by menopause-related cognitive decline. Understanding the additional sociodemographic and mental health-related cognitive decline components, of which few studies have measured, is essential for ensuring the optimal treatment of cognitive decline during the menopause transition.
Choosing and interpreting cognitive tests that are appropriate for diverse target populations is challenging. While most research has shifted away from the original prejudicial creation of cognitive tests, biases still abound in cognitive tests and their interpretation [115]. Basic science and research in cognitive psychology have begun to consider equity and fairness, but the translation of equitable processes to cognitive assessment research and practice is slow [116]. Future studies must include diverse populations and use cognitive tests that will accurately measure cognition in the target population so that the interpretation of the findings is not clouded by test biases. Finally, future studies that include diverse populations must also consider the role of discrimination and racism in cognitive decline [117].
Lastly, the accurate interpretation and comparison of study findings would be facilitated by applying standardized definitions for categorizing women as being in the pre-, peri-, or postmenopausal stages. Current studies have not used a standardized way of classifying women, although most studies have utilized the Stages of Reproductive Aging Workshop+10 criteria [11] along with menstrual bleeding patterns or history and/or a set of endocrine measures. While each criterion serves its purpose, applying a different combination of criteria to categorize women’s menopausal stages may be contributing to inconsistent findings across studies.
Iron supplementation holds promise for alleviating symptoms occurring during the peri- and postmenopausal stages of a woman’s life, including cognitive declines. This relatively cheap and simple intervention may offer a significant way to help women maintain functional ability as they age. This will not only improve the quality of many women’s lives but could also have a positive effect on the economy by reducing the number of missed workdays related to menopause. For these reasons, it is imperative that future studies are conducted to fill the gaps in our understanding. Only then will we be able to determine if iron supplements should be considered as a treatment during the menopause transition.