Background
Despite the widespread use of oral contraceptives (OCs), and the well-documented influence of estrogens, notably 17β-estradiol (E2), on cognition, research relating OCs to working memory is limited and mixed. Two factors may contribute to these mixed findings: 1) pharmacokinetics of oral contraceptives, which drive fluctuations in synthetic hormone levels; and 2) genetic polymorphisms related to dopamine degradation and working memory, which interact with E2. This research investigated whether the pharmacokinetics of oral contraceptives, in concert with the single nucleotide polymorphism (Val158Met; rs4680) of the catechol-o-methyltransferase gene (COMT), influence working memory performance.
Methods
University-age women taking and not taking OCs were tested for working memory and genotyped for COMT. If they were not taking OCs (n = 62), sessions occurred in the early follicular (low E2) and late follicular (high E2) phase. If they were taking OCs (n = 52), sessions occurred 1–2 hours after (high ethinyl estradiol, EE) and ~24 hours after (low EE) pill ingestion. Working memory was tested using the N-back, AX-CPT, Digit Span, and Digit Ordering Tasks. Data were analyzed using multilevel models with estrogen condition, COMT, and group as predictors, controlling for mood and practice effects.
Results
For women taking OCs, time of pill ingestion did not influence performance. However, the subgroup with COMT val/val (low dopamine) were less accurate on 2-back lure trials than those with COMT met/met (high dopamine). For women not taking OCs, cycle phase moderated COMT’s influence on lure accuracy. When compared, women taking OCs had higher AX-CPT proactive control indices than those not taking OCs.
Conclusion
These findings suggest that oral contraceptives are not detrimental for young women’s working memory and that they may increase proactive control. The more pronounced effects of COMT in women taking OCs suggests that, in women taking OCs, suppressed endogenous E2–not fluctuating EE levels–may be more relevant for working memory. Future studies are needed to differentiate effects of endogenous versus synthetic estrogens on working memory.
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.
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