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Ovarian hormones, including 17β-estradiol, are implicated in numerous physiological processes, including sleep. Beginning at puberty, girls report more sleep complaints than boys, which is maintained throughout the reproductive life stage. Sleep problems are exacerbated during the menopausal transition, evidenced by greater risk for sleep disorders. There is emerging evidence that menopause-associated hormone loss contributes to this elevated risk, but age is also an important factor. The extent to which menopause-associated sleep disturbance persists into postmenopause above and beyond the effects of age remains unknown. Untreated sleep disturbances have important implications for cognitive health, as they are emerging as risk factors for dementia. Given that sleep loss impairs memory, an important knowledge gap concerns the role played by menopause-associated hormone loss in exacerbating sleep disturbance and ultimately, cognitive function in aging women. In this review, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining the sleep-wake cycle in younger and middle-aged females, with evidence implicating 17β-estradiol in supporting the memory-promoting effects of sleep. Sleep physiology is briefly reviewed before turning to behavioural and neural evidence from young females linking 17β-estradiol to sleep-wake cycle maintenance. Implications of menopause-associated 17β-estradiol loss is also reviewed before discussing how ovarian hormones may support the memory-promoting effects of sleep, and why menopause may exacerbate pathological aging via effects on sleep. While still in its infancy, this research area offers a new sex-based perspective on aging research, with a focus on a modifiable risk factor for pathological aging.

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Background Ovarian removal via bilateral salpingo‐oophorectomy (BSO) prior to spontaneous menopause (SM) is related to increased Alzheimer’s disease (AD) risk (Rocca et al., 2007). Associative learning deficits are considered the earliest AD symptoms, heralding preclinical AD (Fowler et al., 2002). Performance and brain activation during a face‐name associative memory task differ based on reproductive stage and are linked to fluctuating levels of 17β‐estradiol (E2; Rentz et al., 2017). We hypothesized that BSO would affect memory and functional brain activity during associative encoding. Method Middle‐age women underwent functional magnetic resonance imaging (fMRI) while completing a face‐name associative memory task (Sperling et al., 2003). Recognition performance and brain activation during face‐name pair encoding were assessed in women with BSO taking E2‐based hormone therapy (BSO+E2; n=10; mean age=46), women with BSO taking no hormone therapy (BSO; n=12; mean age=49), age‐matched women with intact ovaries (AMC; n=14; mean age=44), and older women in spontaneous menopause (SM; n=15; mean age=56). Result No group differences in face‐name pair recognition accuracy were found. Multivariate partial least squares analyses (McIntosh & Lobaugh, 2004) revealed significant differences in brain‐behaviour correlations between BSO and SM groups. Accuracy in the SM group correlated positively with activation of the hippocampus, medial temporal, parietal, and frontal lobes, while accuracy in the BSO group correlated negatively with activation of these regions (see Figure). Region‐of‐interest (ROI) analyses revealed that functional activity in the right superior frontal lobe correlated positively with E2 levels in the BSO+E2 group (r=0.83, p=0.01), and negatively with E2 levels in the BSO group (r=‐0.66, p=0.03). Conclusion Activation of distinct brain regions underlying associative memory depends on E2 and age. The BSO group, who experienced menopause approximately 10 years earlier than the SM group, showed significantly different patterns of brain activation compared to the SM group, ultimately to achieve similar recognition accuracy. Importantly, there were no significant differences in performance, indicating that brain changes may precede associative memory changes, and that E2 depletion could play an important role in brain activity underlying women’s associative memory.

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer’s disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17β-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17β-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17β-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

Introduction 17β-estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements. Women have higher risk for AD than men, and those with mid-life 17β-estradiol loss due to surgical menopause, including bilateral salpingo-oophorectomy (BSO) before age 48, have even higher risk. We wondered whether sleep and associative memory in women with BSO (mean age 44–46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β-estradiol-based hormone therapy (ET) might mitigate these effects. Methods We assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1-Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face-name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured. Results BSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET. Conclusion Younger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements. Support (if any) Alzheimer’s Association/Brain Canada Foundation: AARF-17-504715; Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging