Performance on memory-related tasks differs based on the menstrual phase. For example, women perform better on tasks assessing procedural memory, verbal memory, nondeclarative memory, and emotional memory around the time of ovulation, when estradiol levels are elevated (Hampson, 1990a; Maki et al., 2002; Sundström Poromaa and Gingnell, 2014). Further, Ertman et al. (2011) found that levels of progesterone during the menstrual cycle positively correlate with performance on emotional memory free recall and recognition tests. Performance on spatial memory tasks, however, decreases during periods of heightened estradiol and progesterone levels (Hampson, 1990a, b; Phillips and Silverman, 1997; Hausmann et al., 2000). Together, these findings suggest that gonadal hormones contribute to sex differences in memory performance, and that distinct memory domains respond differently to altered hormone levels.

Estrogens and progesterone also influence hippocampal and prefrontal cortex functions that subserve memory. A functional magnetic resonance imaging (fMRI) study found that, when performing a verbal memory task, higher endogenous estradiol concentrations seen in the late follicular phase correlated with greater activation in the left prefrontal cortex (Craig et al., 2008). Konrad et al. (2008) also found greater prefrontal activation while performing a semantic retrieval task during the mid-luteal phase compared to the early follicular phase, which was highly correlated with endogenous estradiol and progesterone levels. Further, cortical activation patterns in the hippocampus and prefrontal cortex associated with verbal and spatial memory are larger in women during the late follicular phase, when estradiol levels are high, compared to women in the earlier follicular phase and with men (Dietrich et al., 2001). While other studies have demonstrated decreased spatial memory performance during menstrual phases with high estradiol levels (Hampson, 1990a, b; Phillips and Silverman, 1997; Hausmann et al., 2000), the differences in results may be related to different studies testing different aspects of spatial memory with different cortical mechanisms (Linn and Petersen, 1985; Postma et al., 1999). Thus, further studies testing different types of memory are needed to better determine which aspects of memory are influenced by these hormones.

The notion that hormonal fluctuations may alter brain function is further supported by evidence of neuronal and structural brain changes in specific phases of the menstrual cycle in humans and in the estrous cycle of the rat. Notably, rodents do not have a menstrual cycle, but rather an estrous cycle that lasts 4–6 days and consists of four phases: proestrus (follicular phase equivalent), estrus (ovulation phase equivalent), metestrus (early luteal phase equivalent), and diestrus (late luteal/menses phase equivalent) with similar fluctuations in hormones as in the human menstrual cycle (Ajayi and Akhigbe, 2020). In rats, dendritic spine density in the hippocampus and overall gray matter volume have been shown to peak around the time of ovulation, paralleling a peak in estradiol levels (Woolley et al., 1990; Woolley and McEwen, 1993; Yankova et al., 2001) and in humans (Hagemann et al., 2011). In women, Protopopescu et al. (2008) found that hippocampal gray matter volume was higher during the late follicular phase compared to those in the late luteal phase. In another study, Lisofsky et al. (2015) observed higher hippocampal gray matter volume and increased functional connectivity between the hippocampus and parietal lobe during the late follicular phase, compared to the early follicular phase. Also, using magnetic resonance imaging, Barth et al. (2016) observed microstructural changes in the hippocampus across the menstrual cycle. With diffusion tensor imaging methods, the investigators found a positive association between serum estradiol concentration and fractional anisotropy and a negative association between estradiol and radial diffusivity (Barth et al., 2016). Together these findings suggest that estradiol may enhance hippocampal gray matter volume and reinforce white matter integrity.

Evidence suggests that hormone levels must be within a specific range to facilitate neurological changes. For example, intermediate concentrations of exogenous estradiol increased hippocampal cell proliferation important for episodic memory in ovariectomized rats, whereas excessively low or high levels did not (Tanapat et al., 2005). Further, administering exogenous progesterone alongside exogenous estradiol to ovariectomized rats attenuated the neuronal propagation observed when administering estradiol alone (Tanapat et al., 2005). Additionally, after applying a progesterone receptor antagonist, the reduction in spine density seen with exogenous progesterone was eliminated (Woolley and McEwen, 1993). Moreover, BDNF, which mediates neuronal plasticity, peaks alongside estradiol during the late follicular and mid-luteal phases (Begliuomini et al., 2007). Therefore, estradiol may promote BDNF-mediated neural plasticity and enhance performance in various memory domains, whereas progesterone may modulate estradiol’s effects and prevent neuronal overgrowth.

These studies illustrate the influence of endogenous and exogenous forms of estrogens and progesterone on brain structure and function that may underlie the memory performance differences seen across the menstrual cycle. Although the fluctuating concentrations of estradiol and progesterone during the reproductive years may not produce neurological changes that significantly impair performance, more extreme fluctuations (e.g., in pregnancy and menopause) may have a more prominent effect on memory consolidation and performance, as discussed below. Importantly, hormonal fluctuations may also indirectly affect memory across the menstrual cycle by altering sleep quality and quantity—a topic to which we now turn.

Sleep duration and quality fluctuate across the menstrual cycle. Women report lower sleep quality during the early follicular and late luteal phases, which correspond to the nadir of estradiol and progesterone levels (Baker and Driver, 2004). Indeed, in women, a reduction in actigraphy-measured sleep efficiency and total sleep time has been observed in the late luteal phase prior to menstruation, when progesterone levels drop (Zheng et al., 2015). In addition, women using oral or vaginally administered contraceptives containing progestin only, or a combined treatment with estradiol, all reported better subjective sleep quality (Guida et al., 2020). Baker et al. (2001) found that women taking various combined oral contraceptives of estradiol and progestin had greater stage 2 sleep compared to placebo or naturally-cycling controls, yet naturally-cycling women in the luteal phase spent more time in SWS compared to those taking oral contraceptives. Therefore, endogenous and exogenous estradiol and progesterone may have different effects on sleep (Baker et al., 2001). Progesterone may exert its effects through GABA receptors located in sleep-wake structures such as the VLPO and POA of the hypothalamus. Progesterone metabolites such as 5α-dihydroprogesterone and 3α-hydroxy-dihydroprogesterone may also enhance sleep by stimulating GABA receptors (Majewska et al., 1986; Gottesmann, 2002; Wang, 2011). Exogenous progesterone decreased wakefulness and latency to NREM sleep and was associated with GABA agonistic metabolites in rats in a dose-dependent manner; however, 5α and 5β pregnanolone did not alter NREM sleep (Lancel et al., 1996). Taken together, both estradiol and progesterone appear to promote sleep quality, with both hormones increasing stage 2 sleep and progesterone increasing SWS. Therefore, progesterone and synthetic progestins may differentially affect sleep (Pluchino et al., 2006). This is important to consider when interpreting the effects of endogenous and exogenous forms of progesterone.

Sleep spindles are one of the hallmark EEG features of stage 2 sleep, and alterations in spindles are among the most-studied aspects of sleep micro-architecture across the menstrual cycle (Genzel et al., 2012). Estradiol and progesterone may both promote sleep spindles, as the highest spindle density is seen during the luteal phase when estradiol and progesterone levels are high. Conversely, the lowest sleep spindle density occurs following menses, when these hormones are low (Ishizuka et al., 1994; Driver et al., 1996; Genzel et al., 2012; Plamberger et al., 2021). In addition, women spend the most time in stage 2 sleep during the early luteal phase (Driver et al., 1996). Taken together, these studies suggest a positive relationship between higher estradiol and progesterone levels seen in the luteal phase and the amount of stage 2 sleep.

Differences in SDB also have been observed across the menstrual cycle, with women exhibiting greater upper airway resistance and a greater number of respiratory events (e.g., hypopneas, apneas, related arousals) during the follicular phase, when progesterone levels are low than in the luteal phase, when levels are high (Driver et al., 2005). Additionally, a study of women undergoing evaluation for daytime sleepiness and suspected SDB found that those with obstructive sleep apnea (apnea-hypopnea index greater >10) had lower progesterone and estradiol levels than those without, after accounting for age, menstrual phase, and menopausal status (Netzer et al., 2003), suggesting that progesterone may protect against SDB. Findings, however, are inconsistent (Stahl et al., 1985), perhaps due to inter-individual differences in gonadal hormone levels across the menstrual cycle (Baker and Lee, 2018). Hormonal fluctuations across a single menstrual cycle are insufficient to produce clinically significant SDB or other sleep disorders, yet it is unknown whether repeated exposure to these variations accumulates across the reproductive years to exert effects on later sleep and brain health.

Overall, findings suggest that fluctuations of estradiol and progesterone alter sleep, with better sleep quantity and quality generally seen during the luteal phase, characterized by higher concentrations of estradiol and progesterone.

A handful of studies have compared sleep-dependent memory consolidation between men and women, including across the menstrual cycles of female participants. Backhaus and Junghanns (2006) found that women had better post-nap declarative memory performance compared to men, whereas Genzel et al. (2012) found that men had better post-nap declarative and motor memory performance compared to women. This conflicting finding may be due, in part, to differences in the menstrual phase of the women selected for each study. Whereas Genzel et al. (2012) only included women during menses, when estradiol and progesterone levels are low, Backhaus and Junghanns (2006) did not control for the menstrual phase. Therefore, better sleep during the luteal phase for some women in the Backhaus and Junghanns study may have partially accounted for the results. Moreover, Genzel et al. (2012) observed that after learning motor and declarative memory tasks, men had an increase in spindle density during a nap, whereas women only exhibited this increase if they were in the mid-luteal phase. They also found that women in the luteal phase and men had a better post-nap performance on these tasks than women in the follicular phase. These findings suggest that hormonal changes associated with the menstrual cycle alter sleep spindle density and thereby affect sleep-dependent memory consolidation. The authors also found that, during the luteal phase, higher estradiol levels were associated with better sleep-dependent declarative memory, whereas higher progesterone levels were associated with greater motor memory consolidation during sleep (Genzel et al., 2012), suggesting these hormones affect performance in different memory domains. Sattari et al. (2017) similarly found a menstrual phase-dependent effect of a nap on memory consolidation of face-name associations. Overall, women had lower performance on a recognition memory task post-nap during their perimenses phase (5 days before to 6 days after the start of menses) compared to their post-nap performance outside of the perimenses phase and that of men. Among the women in the perimenses phase, sleep spindles during the nap were associated with higher memory performance, whereas slow oscillations were not. On the other hand, among women in the non-perimenses phase, slow oscillations rather than sleep spindles during a nap were associated with higher memory performance. Both sleep spindles and slow oscillations are important for memory consolidation and may have specific effects at different points of the menstrual cycle based on estradiol and progesterone concentrations. Further, while sleep spindles may promote memory consolidation regardless of the menstrual phase, spindles and thus memory may be enhanced directly by estradiol and progesterone fluctuations, or indirectly through increased slow oscillation coupling during the luteal phase.

In addition, Plamberger et al. (2021) compared sleep and memory performance among women taking a combined estradiol and progestin pill (dienogest and ethinylestradiol or levonorgestrel and ethinylestradiol), naturally cycling women in their luteal phase, and naturally cycling women in their follicular phase. They found that declarative memory recall improved post-sleep in all women, but overnight improvement was greater in naturally cycling women in their luteal phase and in women taking the combined estradiol/progestin pill, compared to naturally cycling women in their follicular phase (Plamberger et al., 2021). Further, greater sleep spindle density was seen in women taking the combined estradiol/progestin pill and in naturally cycling women during the luteal phase compared to naturally cycling women in the follicular phase (Plamberger et al., 2021). Given that combined estradiol/progestin pills contain high levels of synthetic estradiol and progestin and the luteal phase is characterized by high endogenous levels of these hormones, this further implicates estradiol and progesterone in memory consolidation.

In sum, the effects of sleep on memory formation and consolidation vary depending on the menstrual phase, and both endogenous and exogenous gonadal hormone levels may be driving these differences. During the menstrual cycle, increases in estradiol and progesterone appear to enhance sleep quantity and quality; however, beneficial effects may only result from mild to moderate increases in hormone levels, and markedly elevated hormone levels during pregnancy may have detrimental effects on memory and sleep, as discussed in the next section.

Over 50% of women report memory problems or other cognitive deficits during pregnancy (Janes et al., 1999; Davies et al., 2018). This has led to the colloquial phrase “pregnancy brain” or “baby brain” (Brown and Schaffir, 2019). There is still debate, however, over whether there is a difference in memory performance during pregnancy; some have suggested that cognitive deficits may reflect a cultural stereotype, rather than true deficits (Crawley et al., 2008). Studies have resulted in mixed findings, with some suggesting cognitive impairments and others finding no change in memory performance during pregnancy. For example, Logan et al. (2014) found that while pregnant women had more subjective memory deficits during the third trimester and 3 months postpartum, they did not differ significantly on objective memory tests. Another study found that only nondeclarative memory, tested with an objective word completion priming task, was lower in pregnancy and correlated with subjective decreases in memory performance (Brindle et al., 1991).

Studies in rodents, however, have shown that early pregnancy is associated with memory enhancement, and that later pregnancy is associated with impaired memory performance (Galea et al., 2000; Wilson et al., 2011a; Workman et al., 2012). Because endogenous estrogens and progesterone levels are relatively low in early pregnancy compared to later pregnancy, these findings suggest that moderately elevated levels of progesterone and estrogens are beneficial for memory, whereas markedly high levels are detrimental. Indeed, studies found that pregnant women in their third trimester had lower verbal memory performance compared to pregnant women in their first trimester and non-pregnant controls; moreover, lower performance was associated with higher endogenous estradiol and progesterone levels seen in the third trimester (Glynn, 2010; Wilson et al., 2011a). Despite higher levels of estradiol being associated with better performance during the menstrual cycle, these studies suggest that estradiol improves these domains up to a threshold that is exceeded during pregnancy.

Pregnancy-related changes in cognition and memory are paralleled by changes in brain structure and function. Animal and human studies suggest pregnancy-related changes occur in hippocampal and prefrontal cortex structure and function (Henry and Rendell, 2007; Hoekzema et al., 2017; Barba-Müller et al., 2019). Greater spine density in the CA1 area of the hippocampus and in the prefrontal cortex has been observed in pregnant compared to nonpregnant rats (Kinsley et al., 2006; Cabrera-Pedraza et al., 2017); however, other studies have found no significant pregnancy-related differences in hippocampal brain volumes and even lower amounts of hippocampal neurogenesis among pregnant rats (Galea et al., 2000; Rolls et al., 2008). On the other hand, a neuroimaging study that followed rodents from 3 days before (baseline) to 17 days after mating (equivalent to human third trimester) found structural changes in the hippocampus (Chan et al., 2015). Additionally, in rodents, monoamine neurotransmitter activity decreases in the prefrontal cortex but increases in the hippocampus during pregnancy (Macbeth et al., 2008). This may help explain the more pronounced deficits in domains of memory subserved by the cortex (e.g., episodic memory) in comparison to other forms of memory (e.g., procedural, visual memory) (Wilson et al., 2011a). Overall, results regarding the hippocampal brain changes during pregnancy in rodents remain inconclusive; some have found changes that would indicate pregnancy-induced improvements in memory, while others the opposite. Nonetheless, findings suggest memory performance may differ by pregnancy stage, with the lowest performance seen in the third trimester as sex hormone levels peak.

Although only a few human studies have investigated structural and functional brain changes during pregnancy, they generally suggest a reduction in volumes in several regions during pregnancy which, depending on the brain region, may continue into the postpartum period or return to similar baseline levels. Hoekzema et al. (2017) found reductions in prefrontal gray matter volume, left hippocampal volume, cortical thickness, and surface area (which is believed to be highly sensitive to female sex hormones) shortly after birth compared to pre-pregnancy while nulliparous women demonstrated no changes. Conversely, volumes in areas associated with maternal behavior such as the hypothalamus, amygdala, and substantia nigra have increased shortly after birth (Kim et al., 2010; Barba-Müller et al., 2019). Studies have also shown a decrease in total brain volume during pregnancy that typically reverses in postpartum (Oatridge et al., 2002). However, other studies have found these changes may persist and extend into the postpartum period. Kim et al. (2018) found that prefrontal cortex cortical thickness was positively correlated with months since birth in the first 6 months postpartum. These results may be related to stabilizing hormone levels, which are believed to return to baseline levels around 6 months postpartum. Although, the subregions of the hippocampal gray matter volume return to pre-pregnancy levels, reductions in prefrontal gray matter are maintained up to 2 years postpartum in humans (Hoekzema et al., 2017; Luders et al., 2021). These persistent structural changes may cause residual effects on memory performance 3 months post pregnancy (Glynn, 2010). Further, another longitudinal study rescanned a subsample from the Hoekzema et al. (2017) study, which found reductions in prefrontal gray matter volume, cortical thickness, and surface area 2 years postpartum, again at 6 years postpartum, and found many of the observed gray matter reductions seen shortly after birth were still present 6 years later (Martínez-García et al., 2021). The researchers also commented that while Oatridge et al. (2002) observed an increase in brain volume 6 months postpartum, they did not include a control group of non-pregnant women or consider the number of previous pregnancies to better account for the impact of age and hormonal sensitivity (Martínez-García et al., 2021), which may also be extended to the Kim et al. (2010) study. Taken together, these findings suggest that pregnancy could lead to longstanding and perhaps permanent changes to the maternal brain.

Other researchers have suggested a beneficial effect of pregnancy later in life. In rodents, pregnancy may cause sustained high levels of dendritic density and length in the prefrontal cortex, and increased neurogenesis in the hippocampus (Cabrera-Pedraza et al., 2017; Eid et al., 2019). Moreover, pregnancy-induced memory improvements continue into older age in rats (Love et al., 2005; Macbeth and Luine, 2010). Gatewood et al. (2005) found that rats that had either one or multiple pregnancies performed better on a spatial memory task compared to rats that had never been pregnant. Further, the researchers found that the multiparous rats exhibited less memory decline (and notably, less amyloid precursor protein buildup in the hippocampus) than both primiparous rats and nulliparous rats. This suggests that pregnancy, and perhaps the hormonal fluctuations associated with this time period, may have long-term protective effects on the brain. Evidence for alterations in female sex hormones as the mechanism is supported by similar results from studies in which rats received a pregnancy-mimicking regimen of estradiol and progesterone (Toffoletto et al., 2014).

Moving to human studies, in women, de Lange et al. (2020) used machine learning to identify brain regions susceptible to the effects of pregnancy on brain aging in a sample of almost 20,000 women. The authors found that a greater number of childbirths correlated with lower brain volume reductions, especially for limbic brain regions including the hippocampus. The researchers suggested that the pregnancy-related increases in female sex hormones, cortisol, and anti-inflammatory markers, which fluctuate dramatically during pregnancy and can alter neural plasticity, mediate the observed effects on brain aging (de Lange et al., 2020). On the other hand, while Ning et al. (2020) observed better visual and verbal performance and reduced brain aging in women who had been pregnant, they also found similar results in male partners, suggesting it is not pregnancy per se, but perhaps parenthood that drives these effects. Therefore, more studies are needed to understand the links between the biological aspects of pregnancy to changes in memory and brain aging. Lastly, one study found that pregnancy may be protective for the development of ADRD later in life. Fox et al. (2018) found that a greater number of cumulative months spent in the first trimester over the reproductive lifespan, including periods of miscarriages and terminations, was associated with lower ADRD risk; however, this association was not found for the third trimester, and the second trimester was not measured. Thus, elevated (as seen in the first trimester), but not extremely high estrogens and progesterone levels (as seen in the third trimester), may be responsible for the effects of pregnancy on lowered ADRD risk (Fox et al., 2018). Alternatively, the authors suggested the moderate protective effect of the first trimester may be due to pregnancy-induced alterations in immune function, specifically the increase in regulatory T cells during the first trimester. More studies are needed to investigate the possible role of immune response in early pregnancy in mitigating subsequent ADRD risk.

In sum, whereas findings concerning the effects of pregnancy on objective memory performance and brain structural and functional changes remain mixed in rodents and humans, a majority of studies of subjective memory performance suggest it decreases during pregnancy. In addition, brain changes during and after pregnancy may drive changes in the memory performance. Further longitudinal studies in rodents and humans are needed to characterize how pregnancy alters brain structure and function and how these changes affect memory during pregnancy, postpartum, and later in life. As we discuss in the section that follows, pregnancy is also associated with significant changes in another driver of memory: sleep.

Approximately 75% of pregnant women report poor sleep quality during pregnancy (Mindell et al., 2015). This can be due to factors resulting directly from pregnancy (e.g., frequent need to urinate, uncomfortable sleep positions) and to diagnosable sleep disorders (e.g., insomnia, sleep apnea, and restless legs syndrome) (Mindell et al., 2015). Facco et al. (2010) demonstrated that decreased sleep duration and sleep disturbances are more prevalent in the third trimester compared to the first. Along with greater physical discomfort, steadily increasing estrogens and progesterone concentrations may also degrade sleep in later pregnancy (Silvestri and Aricò, 2019). Changes in sleep architecture have also been observed across pregnancy. During the last 2 months of pregnancy, women may exhibit decreased REM sleep and greater wakefulness after sleep onset (Driver and Shapiro, 1992; Hertz et al., 1992). NREM sleep also decreases across pregnancy (Brunner et al., 1994; Lee et al., 2000). Further, Brunner et al. (1994) found reduced spectral power density in frequencies associated with sleep spindles during the third trimester compared to the first and second in the same women. One study found that greater wakefulness after sleep onset and less time spent in NREM sleep in the third trimester was associated with the increased progesterone levels typically seen during this stage of pregnancy (Wilson et al., 2011b). This is the opposite of what would be expected, given progesterone is thought to have sleep-inducing effects (Majewska et al., 1986), and suggests that extremely high progesterone concentrations could interfere with sleep. As stated by Wilson et al. (2011b), however, progesterone may not be the only factor responsible for these differences; other possible contributors include pregnancy-associated digestive issues, leg cramps, and backache.

Pregnancy can also affect respiration during sleep. Increased endogenous estrogen is thought to cause upper respiratory changes such as mucosal edema and rhinitis, which increase upper airway resistance and may promote SDB (Sharma and Franco, 2004; Morong et al., 2014). The risk of SDB also rises as pregnancy progresses, with the highest risk during the third trimester when estrogens peak (Facco et al., 2014; Pien et al., 2014). On the other hand, a recent study found that progesterone levels were lower in pregnant women with obstructive sleep apnea than those without (Lee et al., 2017), suggesting progesterone may protect against SDB. This is supported by animal studies identifying progesterone as a respiratory stimulant in rats (Bairam et al., 2015). Further, Brownell et al. (1986) found that SDB risk was lower during the third trimester, when progesterone levels are high, compared to postpartum, when progesterone levels decrease dramatically. In sum, pregnancy-related increases in estrogens may contribute to increases in SDB, whereas progesterone may be protective (Venkata and Venkateshiah, 2009).

To our knowledge, the literature on the correlation between pregnancy and later-life sleep patterns is limited. The only such study we identified examined whether snoring during pregnancy predicted later life SDB and failed to find an association (Chaggar et al., 2021).

Although both sleep disturbances and memory complaints are common among pregnant women, studies examining the links between sleep and memory in this population are scarce. One study found that, among pregnant women in their third trimester, those who reported poorer sleep quality had poorer self-rated memory performance, compared to those who reported good sleep quality (Zhang et al., 2021). The authors speculated that estrogens and progesterone may contribute to poor sleep quality in pregnancy, but did not directly investigate these associations. Another study found lower post-sleep verbal memory performance in women in their third trimester compared to those in their first trimester and non-pregnant women. Whereas women in their third trimester had higher progesterone levels, more fragmented sleep, and lower REM sleep and SWS, no associations were observed between progesterone levels and memory performance, and only weak associations were observed between various sleep parameters and memory performance; the authors noted that findings on the lack of a relationship between sleep and memory must be interpreted with caution due to limited variability in memory performance (Wilson et al., 2013). Unfortunately, the study did not consider correlations between progesterone and sleep. Surprisingly, the authors found that spending less time in SWS and longer time in REM was associated with better post-sleep verbal memory performance, contrary to the notion that SWS promotes sleep-dependent memory consolidation (Wilson et al., 2013). The authors speculated that subtle microstructural changes in sleep architecture not evident when using conventional sleep staging methods or changes in estrogen levels (which were unmeasured) may have obscured a relationship between sleep and memory. Thus, the hypothesis that the greater hormonal concentrations seen in pregnancy affect sleep-dependent memory consolidation cannot be dismissed (Wilson et al., 2013). Furthermore, these sleep problems could extend into the postpartum period. Self-report data from a study comparing recently pregnant, primigravid, and nulliparous women support the idea that women who have been pregnant perceive that their memory is poorer, which may be related to subjective sleep changes (Janes et al., 1999). However, objective memory did not differ between the groups in this study (Janes et al., 1999).

Concentrations of the stress hormone, cortisol, may modulate sleep-dependent memory consolidation during pregnancy. In low concentrations, cortisol appears to be beneficial for sleep-dependent memory consolidation; however higher concentrations, such as those seen in pregnancy, could be detrimental to this process and subsequently affect memory performance (Brunner et al., 2006; Akinloye et al., 2013; Bennion et al., 2015). Given elevated cortisol levels also affect sleep, it is plausible that elevated cortisol and concurrently elevated estradiol and progesterone could produce a synergistic effect to produce larger effects on sleep and memory than they do individually (Smith et al., 2009; Duthie and Reynolds, 2013). However, no study has specifically examined these interactions in pregnancy.

In sum, the extent to which memory and sleep are objectively affected during pregnancy remains unclear. Whereas some studies suggest that memory performance worsens slightly during pregnancy and is accompanied by brain changes that may persist and affect memory long after pregnancy, findings from other studies suggest the biological and environmental experience of pregnancy may protect against brain aging and preserve cognition in later life. Brain reductions seen in pregnancy may be a result of prioritizing maternal behavior and priming the maternal brain for motherhood (Brunton and Russell, 2008). The extent to which sleep, which appears to worsen during pregnancy, plays a role in the link between sex hormones and memory also remains unclear.

As the menopausal transition progresses, some declines are observed in subjective and objective memory measures. Specifically, Weber et al. (2012) found that women in the menopausal transition tend to report lower scores on the Memory Functioning Questionnaire, which assesses self-perceptions of everyday memory performance, and while these subjectively rated scores were associated with objective measures of attention and working memory, they did not correlate with objective verbal memory performance (Weber et al., 2012). Yet other studies suggest that objective verbal memory performance declines during the menopausal transition compared to premenopause and this change is associated with declines in estradiol (Nappi et al., 1999; Maki, 2015). Studies have also demonstrated that earlier onset of menopause is associated with faster cognitive decline later in life (Hogervorst, 2013; Shadyab et al., 2017).

The menopausal transition is associated with decreases in both brain metabolic rate and regional activation, which may be attributable to estradiol depletion (Berent-Spillson et al., 2012; Mosconi et al., 2021). Estradiol and progesterone are thought to protect against hypermetabolism and reduced neuronal mitochondrial function in the hippocampus and prefrontal cortex, both of which have been associated with memory decline in menopause and the initial stages of ADRD (Brann et al., 2012; Picard and McEwen, 2014; Siddiqui et al., 2016; Zárate et al., 2017). However, hormone replacement therapy (HRT) does not consistently demonstrate a neuroprotective benefit (Rapp et al., 2003; Shumaker et al., 2003, 2004; Gleason et al., 2015), which may be related to the timing of HRT in relation to the stages of menopause (Rocca et al., 2011). HRT administered in midlife, prior to perimenopause, has been shown to protect against subsequent cognitive impairment (Whitmer et al., 2011), but HRT appears ineffective in this regard or even increases the risk of dementia when administered post-menopause (Rapp et al., 2003; Shumaker et al., 2003, 2004; Gleason et al., 2015). Thus, there may be a “critical window” in which HRT is effective in reducing cognitive decline and AD risk (Maki, 2013). While exact timing remains controversial, an fMRI study demonstrated higher hippocampal activation and verbal memory when HRT was taken during perimenopause compared to matched controls not taking HRT (Maki et al., 2011). Additionally, the “healthy cell bias of estrogen action” hypothesis suggests that cognitive benefits may be seen only when hormone therapy is administered to non-estrogen-deprived cells (i.e., in premenopausal and perimenopausal women) (Brinton, 2005, 2008). The reduced effects of HRT post-menopause could result from the decreased brain sensitivity to estrogens that may occur as menopause progresses (Pike et al., 2009). Responsiveness of estrogen receptor alpha (ERα) and estrogen receptor beta (Erβ) throughout the brain may decrease with age (Ishunina and Swaab, 2008; Waters et al., 2011; Rettberg et al., 2014), perhaps in response to declining endogenous estradiol levels. For instance, whereas ERβ responds to exogenous estradiol in older rats, ERα does not (Waters et al., 2011). Thus, once the ERα is no longer needed, they may irreversibly stop responding to activation. Taken together, these studies suggest that HRT may best be used to target ERβ specifically or as a preventive rather than therapeutic strategy for memory impairment and ADRD (Brinton, 2005, 2008; Waters et al., 2011).

In sum, while some discrepancy still remains, the decreases in estrogens and progesterone during the menopausal transition seem to be associated with and appear to negatively affect verbal memory. In addition, the timing of HRT has important implications for memory, and may most benefit cognition when initiated shortly after the beginning of menopause.

The menopausal transition is frequently accompanied by sleep disturbances. A meta-analysis comparing peri and postmenopausal women to premenopausal women found an age-independent association between menopausal stages and subjective sleep disturbance (Xu and Lang, 2014). Other studies have found that 40%–70% of women report sleep problems during perimenopause, and 20%–30% of these women continue to experience sleep disturbances even after the menopausal transition (Kravitz et al., 2003; Moline et al., 2003; Dzaja et al., 2005; Schüssler et al., 2008). Thus, decreases in hormone levels may have long-lasting effects on sleep duration and quality. Combined estradiol and cyclic progesterone treatment and estradiol-only treatments have been shown to improve self-reported sleep quality in postmenopausal women with vasomotor symptoms (Cintron et al., 2018; Kagan et al., 2018), and this improvement is not fully mediated by the reduction of vasomotor symptoms (Cintron et al., 2018). Therefore, estradiol and progesterone therapy may be treating menopause-associated sleep disturbances unrelated to vasomotor symptoms. For example, non-micronized progesterone and micronized progesterone decreased wake after sleep onset and increased SWS among post-menopausal women experiencing sleep disturbances (Schüssler et al., 2008; Caufriez et al., 2011). Micronized progesterone has also been found to increase REM sleep in postmenopausal women but only during the first third of the night (Schüssler et al., 2008). A study in older postmenopausal women found that women taking one of two synthetic estrone therapies obtained more SWS compared to women not taking estrogen therapy (Moe et al., 2001). Further, compared to estradiol therapy alone, combined estradiol and various progesterone and progestin therapies produced greater improvements in sleep quality in postmenopausal women (Montplaisir et al., 2001; Saletu, 2003; Gambacciani et al., 2005). Though results of HRT trials suggest that HRT increases SWS, longitudinal observational studies have shown increases in SWS sleep in postmenopausal women not taking HRT, while other metrics suggest that HRT increases wakefulness after sleep onset and sleep fragmentation (Lampio et al., 2017; Kalleinen et al., 2021; Matthews et al., 2021). Further, in one study, postmenopausal and perimenopausal women subjectively reported more sleep complaints than premenopausal women, yet obtained more SWS (Young et al., 2003). Other researchers have suggested the increase in SWS may be compensating for increases in sleep fragmentation and poorer sleep quality induced by hormone decreases and age (Brown and Gervais, 2020), but further research is needed to identify the mechanisms. Lastly, studies have identified a higher risk and severity of SDB during and post menopause, which may be related to decreasing estradiol and progesterone levels (Anttalainen et al., 2006; Polo-Kantola, 2007; Mirer et al., 2017). In summary, decreased estradiol and progesterone levels are associated with greater sleep disturbance in the menopausal transition. Although these sleep disturbances may be alleviated by estradiol and progesterone therapy, mechanisms driving improvement remain to be clarified.

Both sleep and memory tend to worsen with age, with poorer outcomes among women compared to men (Soares, 2005; Zhang and Wing, 2006; Li and Singh, 2014; Mazure and Swendsen, 2016). Although studies have begun to address the role of sex hormones in the relationship between sleep and memory in older age, it has not been definitively characterized (Gervais et al., 2017; Hajali et al., 2019). A study found that combined estradiol and HRT, consisting of various progestins, did not improve visual episodic memory performance following sleep deprivation in postmenopausal women (Alhola et al., 2005); however, the menopausal stage at which hormone therapy was initiated was not specified. This may be a critical consideration, given the aforementioned importance of HRT timing for cognitive outcomes. Although the effect of endogenous and exogenous hormones on sleep-loss-induced cognitive deficits remains debated, a substantial literature demonstrates that poorer sleep quality and quantity are associated with cognitive impairment in older women (Blackwell et al., 2006; Yaffe et al., 2011; Diem et al., 2016), which we discuss further below.

With respect to the effects of treatment, estradiol valerate and combined estradiol valerate plus progestin improved subjective and objective sleep quality and cognition in postmenopausal women with insomnia (Saletu, 2003). Further, in an RCT of women randomized to either equine estrogen, transdermal 17β-estradiol therapy, or placebo, Zeydan et al. (2021) found better sleep quality at end of the study (measured by the Pittsburgh Sleep Quality Index Global score) was associated with higher visual attention and executive function among women who received equine estrogen or transdermal 17β-estradiol therapy, but not those in the placebo group. Studies are needed to investigate the extent to which estrogens may modify the effects of sleep on cognition and whether improvements in sleep mediate the effect of HRT on cognition (Saletu, 2003; Zeydan et al., 2021).

Importantly, although aging itself is associated with reductions in sleep-spindle density and in the beneficial effects of spindles on memory consolidation, aging-related changes in spindles may differ between men and women. Martin et al. (2013) found that older men had higher spindle frequency than younger and middle-aged men, whereas older women had lower spindle density compared to younger and middle-aged women. Helfrich et al. (2018), however, found lower sleep spindle density and slow oscillation-spindle coupling were associated with lower episodic memory performance in older men and women and that their younger counterparts had higher spindle density and coupling that was linked to better memory performance. In sum, the extent to which sleep affects memory during and post menopause, and the potential interactions of hormonal changes with sleep with respect to cognition, remain to be clarified by further observational and intervention studies across the menopausal transition.