Cognitive function in association with high estradiol levels resulting from fertility treatment
Introduction
Cognition is a core feature of human brain function, associated at any age with functional performance (Ford et al., 2010). There is an ongoing debate on if and how estradiol (E2) influences cognition. It has been shown to affect actual cognitive performance as well as to influence reparatory mechanisms involved in long-term mental health (Craig & Murphy 2007; Brotfain et al., 2016; Rapp et al., 2003), but study results are controversial.
E2 levels vary during the menstrual cycle and decrease after menopause. Therefore, associations between E2 and cognitive performance are relevant for women's cognitive function during and beyond their reproductive years. Estrogens are one of the most frequently utilized medical drugs. About 151 million women worldwide use contraception containing estrogen, and 12 million women undergo postmenopausal estrogen therapies, most of them over many years (Collaborative Group on Hormonal Factors in Breast Cancer, 2019). At the same time, many women decide against postmenopausal hormone therapy and live 30 or more years with E2 levels that are naturally very low.
It is crucial to improve our understanding of regulatory mechanisms and strategies for adequate cognitive function. Understanding of the impact of E2 on cognitive performance will help health professionals to improve counselling on hormonal treatment and to target appropriate E2 levels.
Several epidemiologic and physiologic studies support an association between high E2 levels and better cognitive performance. For example, cognitive control and verbal and spatial memory are reported to improve, and the number of working memory errors produced on the spacial working memory has been found to be reduced during high E2 phases of the menstrual cycle (Hampson and Morley, 2013; Sundström Poromaa and Gingnell, 2014). Pregnant women, who have E2 levels above the maximum level of a menstrual cycle, show working memory performance that equals or even significantly exceeds the performance of non-pregnant controls matched for age and educational level (Hampson et al., 2015).
Cognitive changes related to attention, memory, and processing speed after menopause, i.e. when E2 levels drop, are greater than would be expected from the effects of age alone (Halbreich et al., 1995). The menopausal transition is accompanied by mild deficits in concentration and processing speed (Kok et al., 2006), but various factors other than hormonal changes are presumably involved (e.g., impaired sleep quality). In a 14-year longitudinal study of 403 women during menopausal transition, verbal recall declined independently from normal aging (Epperson et al., 2013). Other studies indicating a supporting role of estrogen for cognitive performance in postmenopausal women corroborate such findings (Albert & Newhouse, 2019; Henderson, 2008; Rettberg et al., 2014; Russell et al., 2019). Cognitive impairment in women who experience a longer period with low ovarian hormone levels because of early menopause without hormone therapy or higher parity further reinforces the negative impact of estrogen decline (Georgakis et al., 2016; Rocca et al., 2007; Sherwin, 1988; Song et al., 2020).
However, other results indicate only a small or neglible effect of E2 on cognitive function. When compared to non-pregnant women, pregnant women show estrogen-related differences only in working memory but no significant differences in other cognitive functions, i.e. memory, attention and object recognition processes (Hampson et al., 2015). Menopausal status (early and late menopausal transition and early and late postmenopause) was not related to significant differences in episodic verbal memory measured by a supraspan word list recall task (Henderson et al., 2003). In the Study of Women's Health Across the Nation (SWAN), 2362 women aged 42–52 years observed longitudinally for 4 years showed improvement in verbal memory in pre- and postmenopause, but not in early or late perimenopause, i.e., the ability to learn may be compromised only temporarily (Greendale et al., 2009). In our own prospective longitudinal study, incorporating data from 2 consecutive menstrual cycles, we did not find a consistent and robust association between repeated measurements of estrogen and cognitive function, including working memory, attention, and cognitive bias (Leeners et al., 2017).
In line with these findings, attempts to reduce the prevalence of postmenopausal cognitive impairment by hormone therapy have not shown the desired outcome (Shumaker et al., 2003). Although there is evidence of a neuroprotective effect of E2 (Brotfain et al., 2016; Rapp et al., 2003), and estrogen deprivation is associated with the risk for Alzheimer's disease (Russell et al., 2019), several large studies failed to show a beneficial effect, or even found an unfavorable effect, of estrogen therapy on cognitive performance (Henderson et al., 2016; Rapp et al., 2003; Shumaker et al., 2003, Shumaker et al., 2004; Kantarci et al., 2018). Late initiation of estrogen therapy relative to age at menopause is one of the factors discussed that explain this finding (Espeland et al., 2004; Resnick et al., 2006; Shumaker et al., 2003).
Many studies investigating cognitive performance in relation to the menstrual cycle have flaws, which can lead to false-positive results (Leeners et al., 2017). Critical methodological issues include the lack of standardization of cycle phases, a lack of confirmation of the cycle phase through hormonal measurements, the timing of assessments within the menstrual cycle, the choice of tests to evaluate cognition, and many more. Available studies are very heterogeneous with regard to selected tests, and many studies have explored only one or a few aspects of cognitive function. Another major flaw is the investigation of the combined effects of E2 and progesterone, as findings may be biased by an interactional effect of both hormones (Toffoletto et al., 2014).
In women, the highest proportion of systemically available E2 is produced by growing follicles, which contain the human oocyte. During the follicular phase of the menstrual cycle, E2 levels rise from less than 200 pmol/l to about 800-900 pmol/l, secreted by a preovulatory follicle (Taylor et al., 2019). In the context of fertility treatment, E2 reaches levels significantly above those in a natural menstrual cycle, as the aim is to achieve not only 1 but rather between 5 and 15 mature oocytes, each of which contributes to the E2 level. While E2 values rise steadily to their maximum, where they persist for several days, other ovarian hormones remain stable. Therefore, in addition to studies in the menstrual cycle, the significant rise of E2 during the 9–13 day stimulation period in the context of fertility treatment represents a good quasi-experimental model to evaluate the isolated role of natural, but supraphysiological E2 levels in cognitive function.
We therefore benefited from this model to investigate the association between the two significantly different E2 levels and women's cognitive performance. Based on the literature, we expected that supraphysiological estrogen levels would influence cognitive function. Specifically, our hypothesis was that cognitive performance would be better at the end of the stimulation phase, when E2 levels are high. We expected attention, visual memory, and executive functions to be improved when maximum E2 levels were present at the end of a stimulation phase of fertility treatment.
Associations between E2 and cognitive function were evaluated (i) as scores per time period and (ii) as score changes over time. We also assessed (iii) whether associations between E2 and cognitive function were similar when different prefrontal and reticular regulatory systems were involved.
Section snippets
Participants and design
We conducted a prospective quasi-experimental observational study investigating serial measurements of hormonal and neurocognitive parameters in 44 women receiving in vitro fertilization at the Department of Reproductive Endocrinology in Zurich, Switzerland. The study is part of a project designed to model hormonal changes in women and their association with neuropsychological function and emotion regulation (Hengartner et al., 2017; Leeners et al., 2017, Leeners et al., 2019).
This study
Cognitive functions in relation to estrogen levels per measurement occasion
Mean scores in cognitive functions and estrogen levels at both measurement occasions are shown in Table 1. Cognitive test scores did not vary during fertility treatment except for cancellation screen, which improved over time (p < .001). As expected, estrogen scores increased dramatically from the first to the second assessment (p < .001).
Next we tested overall associations between cognitive functions and estrogen levels using two different GEE models (see Table 2). In Model 1, we computed only
Discussion
Fertility treatments provide the possibility of using a unique quasi-experimental model to evaluate substantial changes in E2 levels and their impact on cognitive functions. Contrary to our hypothesis, this study showed no association between low and high E2 phases of an in vitro fertilization treatment and cognitive performance as measured by tests on attention, visual memory, and executive functions. Results covering cognitive function regulated in the frontal lobe and the reticular formation
Conclusions
Although within our study design we could compare cognitive performance at two notably different levels of E2 without modification of any other parameter, neither the total group, nor the individual women, nor the direct investigation of associations with hormone values has shown any variation in cognitive performance. As evaluation of cognitive performance was evaluated using a series of established tests, which cover a broad spectrum of cognitive functions and associated brain regions, our
CRediT authorship contribution statement
BL, MH, TK: Conceptualization; KG, DW, MH: Data curation; MH Formal analysis. BL, MH, TK, ET, TM, FI, ME, SR: Funding acquisition. BL, TK, KG, DW, CS, LS: Investigation. BL, MH, TK: Methodology. BL, ET, FI, ME: Project administration. BL, TK, ET, TM, FI, ME, SR: Resources. MH, FI: Software. BL, TK: Supervision. MH, KG: Validation. BL, MH: Visualization. BL, MH, TK: Roles/Writing - original draft. BL, MH, TK, KG, ET, TM, FI, ME, SR, DW, LS, CS: Writing - review & editing.
Declaration of competing interest
None.
Acknowledgements
We thank all study participants for supporting our research as well as Dr. Hans Jürg-Casall for providing neuropsychological expertise in the preparation of this manuscript.
Funding
The evaluation of the hormonal parameters was supported by a European Union 7th Framework Programme grant (PAEON 600773), and the neuropsychological testing was supported by the Bangerter-Rhyner Foundation. The sponsors had no further role in the experimental design, the collection, analysis, and interpretation of data, the drafting of this report, or the decision to submit this paper for publication.
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First and second authors have contributed equally to the manuscript.