Natural vs. Surgical Postmenopause and Psychological Symptoms Confound the Effect of Menopause on Executive Functioning Domains of Cognitive Experience
Abstract
Objective:
The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause.
Study Design:
A cross-sectional sample of women aged 35–65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES—D).
Main Outcome Measures:
We analyzed the association between group and BADDS scores using linear regression models – first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2).
Results:
In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2).
Conclusions:
The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.
Reprinted from Maturitas 2023; 170:64–73, with permission from Elsevier. Copyright © 2023
Introduction
The menopause transition involves dramatic changes in levels of reproductive hormones and functioning of the hypothalamic-pituitary-ovarian axis. During this time, women frequently report struggles with aspects of cognition, including learning, memory, and executive functioning. Executive functioning domains of cognition include initiating and sustaining focus on tasks, temporarily retaining and utilizing information (working memory), processing speed, and motivation for work [1–4]. These executive functioning cognitive domains are especially relevant to the menopause transition because they are highly dependent on the prefrontal cortex (PFC), the neural structure and function of which is modulated by ovarian hormones such as estradiol [5–7]. However, the majority of research into the effects of the menopause transition on cognition have focused on domains of learning and memory, as opposed to exclusively examining executive functioning.
On learning and memory tasks, perimenopausal and postmenopausal women show poorer performance compared to premenopausal women, independent of age [1,8–10]. However, the findings in this literature are inconsistent as to whether these cognitive difficulties persist past perimenopause or if they resolve in postmenopause. One longitudinal study found that cognitive difficulties peak during perimenopause and recover in postmenopause to premenopausal levels [8]. Other longitudinal studies found that the perimenopausal decline in cognitive function does not recover or only partially recovers in postmenopause compared to premenopausal levels [1,11]. With the negative impact that cognitive difficulties have on quality of life, it is critical to determine what factors contribute to these symptoms during the menopause transition and what domains are most affected. The present study investigates how confounders, such as the type of postmenopause (natural vs. surgical) and current psychological symptoms, impact domains of executive functioning in different stages of menopause.
Natural and surgical postmenopause are distinct experiences with differing effects on cognitive function. Surgical postmenopausal women show more cognitive impairments compared to natural postmenopausal women, independent of age [12–14]. Several differences between natural and surgical postmenopause provide rationale for why cognitive dysfunction is relatively more pronounced following surgical postmenopause. First, the most common indication for surgical menopause (bilateral oophorectomy) is as part of gynecological or breast cancer care or risk reduction, necessitating procedures that induce an abrupt and permanent cessation of ovarian hormone production compared to the natural menopause transition [15]. Second, surgical menopause often occurs before women have entered perimenopause, resulting in an earlier age at postmenopause [16], and earlier postmenopause age is associated with poorer performance on verbal fluency and visual memory tasks [17]. Third, women who undergo surgical menopause as part of cancer care may experience cognitive impairments related to having cancer and/or undergoing chemotherapy [18,19]. Thus, postmenopause type (natural vs. surgical) is important to consider when studying cognition across menopause stages. However, studies about cognition and the menopause transition often exclude participants with surgical postmenopause, group natural and surgical postmenopause together, or include relatively small sample sizes of surgical postmenopausal women [8,11,20].
Psychological symptoms (e.g., disrupted sleep, increased anxiety and depression) also confound the relationship between cognition and menopause stage/type, as these symptoms commonly occur across the menopause transition [21,22] and negatively impact cognitive functioning [23,24]. More specifically, disrupted sleep, anxiety, and depression also negatively impact PFC-dependent executive functions [25–27]. However, studies control for these psychological variables inconsistently, which may help explain the observed variability among findings as to whether cognitive problems persist into postmenopause. Furthermore, the prevalence of symptoms that negatively impact cognition, such as depression and anxiety, is higher in women who underwent surgical menopause compared to age-matched women who did not have a bilateral oophorectomy [28]. Despite this evidence, at present, no previous studies have investigated executive functioning and the menopause transition while accounting for possible confounding effects of both postmenopause type and psychological symptoms.
The purpose of this research is to investigate within the same study whether postmenopause type (natural or surgical) and current psychological symptoms (difficulty sleeping, anxiety, and depression) account for the persistence or recovery of cognitive difficulties, specifically executive functioning domains, in postmenopause. We utilized the Brown Attention Deficit Disorder Scale (BADDS) [29] to assess executive functioning in premenopausal, perimenopausal, and natural and surgical postmenopausal women. The BADDS is a validated self-report measure of symptoms of attention hyperactivity deficit disorder (ADHD) that captures multiple domains of executive functioning [30]. The BADDS has previously been used to assess executive dysfunction during the menopause transition and the effectiveness of pharmaceutical treatments aimed at improving executive function [2,24,31,32]. We analyzed the effect of menopause stage and type (premenopause, perimenopause, and natural and surgical postmenopause) on BADDS scores, with and without controlling for possible confounding variables, to better understand the relationship between the menopause transition and self-reported cognitive complaints and why discrepancies in the literature exist about the persistence of these cognitive difficulties, including executive dysfunction.
Methods
Participants
We used convenience sampling to recruit biological females ages 35–65. To sufficiently sample women who had undergone surgical menopause, we recruited participants from ResearchMatch with hereditary cancer risk who were affiliated with the Facing Our Risk of Cancer Empowered (FORCE) group (https://www.facingourrisk.org/). We also recruited participants from listservs at the Penn Center for Women’s Behavioral Wellness. To be eligible, participants were required to live in the United States, be able to speak and read English, and not be currently pregnant or breastfeeding.
At the start of the online survey, participants were provided with information about the study including contact information for study staff and the Office of Clinical Research at the University of Pennsylvania. Participants were then asked to respond to the question “Do you agree to take part in this study?” with the option to provide consent to participate by selecting “Yes, I agree to take part in this study”, or to select “No, I do not agree to take part in this study”, in which case they were not asked any further questions. The study was approved by the University of Pennsylvania and the University of Colorado Anschutz Medical Campus human investigations review boards.
Measures
Menopause stage and type.
Participants self-selected their menopause stage based on terminology from the 2001 Stages of Reproductive Aging Workshop (STRAW) [33] (summarized in Table 1; full wording is available in Supplementary Materials). Women who identified as postmenopausal were also asked whether their transition to postmenopause was natural or surgical. Women who reported having experienced premature ovarian failure, primary ovarian insufficiency, chemical menopause after chemotherapy or radiation, or any type of menopause other than natural or surgical (bilateral oophorectomy) were excluded from the study.
| Stage | Menstrual cycle criteria |
|---|---|
| Premenopause | Relatively regular menstrual cycles |
| | Absence of menopausal symptoms such as hot flashes and night sweats |
| Perimenopause | Either a fewer or greater number of days between menstrual periods |
| | Possible presence of menopausal symptoms such as hot flashes and night sweats |
| Postmenopause | Absence of a menstrual period for 12 months or more |
Medical history.
Participants completed a questionnaire about their medical history, including yes/no questions about whether they had a history of cancer or had received chemotherapy. Diagnosis of ADHD and difficulty sleeping were determined by categorical (yes/no) responses to the questions: “Have you been diagnosed with Attention Deficit Hyperactive Disorder (ADHD)?” and “Do you have difficulty sleeping?” (Table 2). Women with a history of brain cancer, a brain tumor, or meningioma were excluded from analyses.
| Variable | N with data | Overall (N = 1971) | Pre (N = 597) | Peri (N = 331) | Natural Post (N = 724) | Surgical Post (N = 319) | p value |
|---|---|---|---|---|---|---|---|
| Age (years) (mean ± SD) | 1914 | 51.5 (8.7) | 42.2 (4.3) | 49.0 (4.4) | 59.0 (4.3) | 54.2 (7.9) | <0.001 |
| BMI (mean ± SD) | 1967 | 29.2 (7.8) | 28.8 (8.0) | 30.3 (8.2) | 28.3 (7.2) | 31.0 (7.7) | <0.001 |
| Ethnicity | 1964 | | | | | | 0.153 |
| Hispanic/Latino descent | | 91 (4.6 %) | 37 (6.2 %) | 17 (5.1 %) | 23 (3.2 %) | 14 (4.4 %) | |
| Not Hispanic/Latino | | 1873 (95.0 %) | 558 (93.5%) | 313 (94.6 %) | 697 (96.3 %) | 305 (95.6 %) | |
| Race | 1961 | | | | | | 0.041 |
| White | | 1705 (86.9 %) | 498 (84.1%) | 285 (86.6 %) | 648 (89.8 %) | 274 (86.2 %) | |
| Black/African American | | 118 (6.0 %) | 38 (6.4 %) | 17 (5.2 %) | 38 (5.3 %) | 25 (7.9 %) | |
| American Indian/Alaska Native | | 7 (0.4 %) | 3 (0.5 %) | 1 (0.3 %) | 1 (0.1 %) | 2 (0.6 %) | |
| Others/multiracial | | 131 (6.7 %) | 53 (9.0 %) | 26 (7.9 %) | 35 (4.8 %) | 17 (5.3 %) | |
| Marital status | 1966 | | | | | | <0.001 |
| Single (never married) | | 331 (16.8 %) | 165 (27.6%) | 48 (14.5 %) | 92 (12.7 %) | 26 (8.2 %) | |
| Married or domestic partnership | | 1179 (59.8 %) | 338 (56.6%) | 218 (65.9 %) | 407 (56.2 %) | 216 (67.7 %) | |
| Widowed | | 51 (2.6 %) | 6 (1.0 %) | 5 (1.5 %) | 34 (4.7 %) | 6 (1.9 %) | |
| Divorced | | 370 (18.8 %) | 77 (12.9 %) | 51 (15.4 %) | 179 (24.7 %) | 63 (19.7 %) | |
| Separated | | 35 (1.8 %) | 10 (1.7 %) | 8 (2.4 %) | 9 (1.2 %) | 8 (2.5 %) | |
| Education | 1968 | | | | | | <0.001 |
| Less than college degree | | 559 (28.4 %) | 142 (23.8%) | 90 (27.3 %) | 205 (28.4 %) | 122 (38.2 %) | |
| College graduate | | 626 (31.8 %) | 178 (29.9%) | 123 (37.3 %) | 224 (31.0 %) | 101 (31.7 %) | |
| Graduate degree | | 783 (39.8 %) | 276 (46.3%) | 117 (35.5 %) | 294 (40.7 %) | 96 (30.1 %) | |
| Household income | 1971 | | | | | | 0.001 |
| <$50,000 | | 472 (23.9 %) | 135 (22.6%) | 60 (18.1 %) | 180 (24.9 %) | 97 (30.4 %) | |
| $50,000 to $100,000 | | 667 (33.8 %) | 213 (35.7%) | 111 (33.5 %) | 232 (32.0 %) | 111 (34.8 %) | |
| $100,000 to $200,000 | | 620 (31.5 %) | 203 (34.0%) | 117 (35.3 %) | 224 (30.9 %) | 76 (23.8 %) | |
| >$200,000 | | 146 (7.4 %) | 37 (6.2 %) | 29 (8.8 %) | 55 (7.6 %) | 25 (7.8 %) | |
| Unknown or did not-disclose | | 66 (3.3 %) | 9 (1.5 %) | 14 (4.2 %) | 33 (4.6 %) | 10 (3.1 %) | |
| Has ever had cancer | 1971 | | | | | | <0.001 |
| Yes | | 275 (14.0 %) | 34 (5.7 %) | 35 (10.6 %) | 106 (14.6 %) | 100 (31.3 %) | |
| No | | 1696 (86.0 %) | 563 (94.3%) | 296 (89.4 %) | 618 (85.4 %) | 219 (68.7 %) | |
| Chemotherapy for any cancer | 1971 | 73 (3.7 %) | 12 (2.0 %) | 5 (1.5 %) | 20 (2.8 %) | 36 (11.3 %) | <0.001 |
| Has difficulty sleeping | 1971 | 1240 (62.9 %) | 338 (56.6%) | 237 (71.6 %) | 443 (61.2 %) | 222 (69.6 %) | <0.001 |
| Has been diagnosed with ADHD | 1971 | 203 (10.3 %) | 71 (11.9 %) | 53 (16.0 %) | 48 (6.6 %) | 31 (9.7 %) | <0.001 |
| Meets GAD-7 criteria for anxiety | 1971 | 481 (24.4 %) | 159 (26.6%) | 100 (30.2 %) | 123 (17.0 %) | 99 (31.0 %) | <0.001 |
| Meets CES-D criteria for depression | 1971 | 473 (24.0 %) | 139 (23.3%) | 103 (31.1 %) | 135 (18.6 %) | 96 (30.1 %) | <0.001 |
| Age at final menstrual period (FMP) (years) (mean ± SD) | n/a | n/a | n/a | n/a | 49.7 (5.3) | 40.8 (7.8) | n/a |
Executive function.
The Brown Attention Deficit Disorder Scale (BADDS) [29] is a 40-item questionnaire that assesses five subscales of executive functioning (summarized in Table 3):
| Scale | Description | Number of items | Score range |
|---|---|---|---|
| Total | Summary of all subscales | 40 | 0–120 |
| Subscale 1 | Organizing and activating to work | 9 | 0–27 |
| Subscale 2 | Sustaining attention and concentration | 9 | 0–27 |
| Subscale 3 | Sustaining energy and effort | 9 | 0–27 |
| Subscale 4 | Managing affective interference | 7 | 0–21 |
| Subscale 5 | Utilizing working memory and accessing recall | 6 | 0–18 |
Subscale 1: Organizing and Activating for Work. Nine items assessed excessive difficulties in getting organized, getting started on work-related tasks, and self-activating for daily routines.
Subscale 2: Sustaining Attention and Concentration. Nine items assessed chronic problems in sustaining attention when doing work-related tasks, such as excessive daydreaming or distractibility when listening or doing required reading, or repeatedly losing track and needing to re-read assigned material.
Subscale 3: Sustaining Alertness, Effort, and Processing Speed. Nine items assessed problems in keeping up consistent alertness and effort for work-related tasks, daytime drowsiness, slow processing of information, or inadequate task completion.
Subscale 4: Managing Affective Interference. Seven items assessed difficulties with mood, sensitivity to criticism, lack of motivation, excessive frustration, or discouragement.
Subscale 5: Using Working Memory and Accessing Recall. Six items assessed issues with forgetfulness in daily tasks and routines, problems in recall of learned material, and losing track of necessary items.
For each item in the questionnaire, participants reported the extent to which it had been a problem over the last six months (0=never, 1=once a week or less, 2=twice a week, or 3=almost daily). Total BADDS scores range from 0 to 120, with higher scores indicating more self-reported difficulties with executive functioning.
Anxiety.
Participants completed the Generalized Anxiety Disorder Questionnaire (GAD-7) to assess the presence and severity of anxiety symptoms. A score of ≥10 represents moderate to severe anxiety symptoms and the cutoff for clinically significant anxiety [34,35]. We grouped participants with a GAD-7 score ≥ 10 as those who met the clinical cutoff for anxiety and those with a score < 10 into those who did not (Table 2).
Depression.
Participants completed the Center for Epidemiologic Studies Depression Scale (CES—D) to assess the presence and severity of depression symptoms. A score of ≥ 16 represents the cutoff for clinical depression in the general population [36]. We grouped participants with a CES-D score ≥ 16 into those who met the cutoff for clinically significant depression and those with a score < 16 into those who did not (Table 2).
Statistical Analysis
BADDS validation.
We tested the internal validity of the BADDS assessment in our sample of women in premenopause, perimenopause, and natural or surgical postmenopause by running Pearson’s correlations between total BADDS scores and scores for each of the five subscales (Table 4), with the hypothesis that if the measurement were valid, total BADDS scores and subscale scores should be highly positively correlated with one another (i.e., participants who scored highly on one subscale would likely score highly on other subscales as well).
| | Total | Subscale 1 | Subscale 2 | Subscale 3 | Subscale 4 | Subscale 5 |
|---|---|---|---|---|---|---|
| Total | 1.00*** | 0.92*** | 0.87*** | 0.89*** | 0.76*** | 0.81*** |
| Subscale 1 | 0.92*** | 1.00*** | 0.73*** | 0.82*** | 0.66*** | 0.65*** |
| Subscale 2 | 0.87*** | 0.73*** | 1.00*** | 0.68*** | 0.55*** | 0.69*** |
| Subscale 3 | 0.89*** | 0.82*** | 0.68*** | 1.00*** | 0.63*** | 0.67*** |
| Subscale 4 | 0.76*** | 0.66*** | 0.55*** | 0.63*** | 1.00*** | 0.50*** |
| Subscale 5 | 0.81*** | 0.65*** | 0.69*** | 0.67*** | 0.50*** | 1.00*** |
Numbers indicate the Pearson’s r correlation between items in the matrix. *** p < 0.001.
Linear regression models.
To analyze the effect of menopause group on BADDS scores, we ran linear regression models with premenopause, perimenopause, natural postmenopause, and surgical postmenopause as predictors for each of the BADDS outcome variables (total BADDS and five subscale scores) separately and conducted pairwise comparisons between the four menopause groups, adjusting for multiple comparisons using the Bonferroni correction (α = 0.0083).
Covariate selection.
All models included current age and education as covariates, as these variables have been shown to impact BADDS scores independent of menopausal stage/type [11,20] and are frequently included as covariates in analyses of executive functioning [17,20]. All models also included ADHD as this condition impacts BADDS scores [30].
The first linear regression model (Model #1) only included age, education, and ADHD as covariates. In addition to these covariates, the second linear regression model (Model #2) also included difficulty sleeping (self-report), anxiety symptom severity (GAD-7 score), and depression symptom severity (CES-D score) to test whether these variables confounded the effect of menopause group on BADDS scores observed in Model #1 (Figure 1). We report associations in the form of unstandardized regression coefficients, β, from the multivariable linear regression models. Statistical analyses were performed in R version 4.2.0 [37].
Results
Participants
Demographic data for study participants is presented overall and by menopause group in Table 2. Based on the self-selection criteria for menopause stage and type, women were divided into premenopause (N= 597), perimenopause (N=331), natural postmenopause (N=724), and surgical postmenopause (N=319) groups. Most participants were White (86.9 %), not Hispanic/Latino (95.0 %), and married or in a domestic partnership (59.8 %). The most represented level of education and household income was a graduate degree (39.8 %) and $50,000–$100,000 (33.8 %), respectively. A history of cancer was present in 14.0% of participants. Raw means for each group, prior to adjusting for any covariates, are presented in Figure S1 in the online supplement.
The number of participants in each menopause group who reported a diagnosis of ADHD, difficulty sleeping, and clinically significant levels of anxiety or depression are presented in Table 2. Perimenopausal women and surgical postmenopausal women had the highest prevalence of difficulty sleeping, anxiety, and depression, while the prevalence was lowest in premenopausal and natural postmenopausal women.
Validation of BADDS Among the Study Sample
Covariate Selection
Given the possibility that a history of cancer and/or chemotherapy could impact executive functioning [18,39,40], we tested for their associations with BADDS scores. We first analyzed the effect of cancer and chemotherapy on BADDS scores in separate unadjusted linear regression models. Cancer history was not significantly associated with total BADDS score (p=0.573) or any of the five subscale scores (p≥0.074). Chemotherapy history was significantly associated with total BADDS score (p=0.036) and Subscale 5 (p=0.001). However, when chemotherapy history was included as a covariate in the model with menopause group, age, education, and ADHD, it no longer had a significant effect on total BADDS score (p=0.133). Therefore, cancer and chemotherapy histories were not included as covariates in our analyses.
Previous studies have shown that an earlier postmenopausal age and a longer time in postmenopause are both associated with greater cognitive impairments [17,41]. Surgical postmenopausal women had a younger average age at final menstrual period (FMP) than natural postmenopausal women (40.8 vs. 49.7 years; Table 2). However, we did not include age at FMP or time since FMP as a covariate in our models for several reasons. First, FMP data were only available for the natural and surgical postmenopausal groups and therefore could not be included in our models, all of which compared these groups with premenopausal and perimenopausal women. Second, in analyses comparing only natural and surgical postmenopausal groups, current age had a stronger association with BADDS scores than age at FMP or time since FMP, likely due to the cross-sectional nature of this study. Therefore, we adjusted for current age rather than age at FMP or time since FMP.
Effects of Menopause Stage and Type on BADDS Scores
Model #1: controlling for age, education, and ADHD.
Model #1 examined the effect of menopause group on BADDS scores, adjusting for age, education, and ADHD (F7,1903 = 43.49; p < 0.001; adjusted R2 = 0.14). Menopause group significantly impacted total BADDS score (F3,1903 = 27.37, p < 0.001), as well as BADDS scores on each of the subscales (Subscale 1 [organizing and activating to work]: F3,1903 = 23.53, p < 0.001; Subscale 2 [sustaining attention and concentration]: F3,1903 = 23.25, p < 0.001; Subscale 3 [sustaining energy and effort]: F3,1903 = 24.16, p < 0.001; Subscale 4 [managing affective interference]: F3,1903 = 19.35, p < 0.001; Subscale 5 [utilizing working memory and accessing recall]: F3,1903 = 21.92, p < 0.001).
Pairwise comparisons between groups for Model #1 are presented in Table 5 (Bonferroni corrected at α = 0.0083). Compared to premenopausal women, perimenopausal women had a total BADDS score that was 11.13 points higher (p < 0.001), as well as significantly higher scores on each subscale (p < 0.001). Natural postmenopausal women had a total BADDS score that was 8.18 points higher than premenopausal women (p < 0.001), as well as significantly higher scores on each of the subscales except for Subscale 3. No significant differences emerged between perimenopausal women and natural postmenopausal women.
| Comparison → | Peri – pre | Natural post – pre | Natural post – peri | |||
|---|---|---|---|---|---|---|
| Outcome ↓ | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value |
| BADDS total score | 11.13 (7.29, 14.97) | <0.001 | 8.18 (3.46, 12.90) | <0.001 | —2.95 (—7.03, 1.13) | 0.156 |
| Subscale 1 | 2.33 (1.33, 3.33) | <0.001 | 1.94 (0.71, 3.17) | 0.002 | —0.38 (—1.44, 0.68) | 0.479 |
| Subscale 2 | 2.62 (1.61, 3.63) | <0.001 | 1.99 (0.75, 3.23) | 0.002 | —0.63 (—1.70, 0.44) | 0.245 |
| Subscale 3 | 2.27 (1.37, 3.17) | <0.001 | 1.25 (0.14, 2.36) | 0.028 | —1.02 (—1.98, —0.06) | 0.036 |
| Subscale 4 | 2.07 (1.32, 2.82) | <0.001 | 1.46 (0.54, 2.38) | 0.002 | —0.61 (—1.40, 0.19) | 0.133 |
| Subscale 5 | 1.84 (1.18, 2.51) | <0.001 | 1.54 (0.72, 2.36) | <0.001 | —0.30 (—1.01, 0.40) | 0.403 |
| Comparison → | Surgical post – pre | Surgical post – peri | Surgical post – natural post | |||
|---|---|---|---|---|---|---|
| Outcome ↓ | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value |
| BADDS total score | 15.75 (11.29, 20.21) | <0.001 | 4.62 (0.44, 8.80) | 0.030 | 7.57 (3.98, 11.16) | <0.001 |
| Subscale 1 | 3.86 (2.70, 5.02) | <0.001 | 1.53 (0.44, 2.62) | 0.006 | 1.92 (0.98, 2.85) | <0.001 |
| Subscale 2 | 3.95 (2.78, 5.12) | <0.001 | 1.33 (0.24, 2.43) | 0.017 | 1.97 (1.02, 2.91) | <0.001 |
| Subscale 3 | 2.77 (1.72, 3.81) | <0.001 | 0.50 (—0.48, 1.48) | 0.32 | 1.52 (0.68, 2.36) | <0.001 |
| Subscale 4 | 2.27 (1.40, 3.14) | <0.001 | 0.20 (—0.61, 1.02) | 0.627 | 0.81 (0.11, 1.51) | 0.023 |
| Subscale 5 | 2.90 (2.13, 3.68) | <0.001 | 1.06 (0.33, 1.78) | 0.004 | 1.36 (0.74, 1.98) | <0.001 |
Differences were calculated based on estimated marginal means controlling for age, education, and ADHD. Significance was adjusted for multiple comparisons at α =0.0083 using the Bonferroni correction. Bolded effects indicate p < 0.0083.
Women who underwent surgical menopause had a total BADDS score that was 15.75 points higher compared to premenopausal women (p < 0.001), as well as higher scores on each of the subscales (p < 0.001). Between surgical postmenopausal women and perimenopausal women, there was no significant difference in total BADDS score (p = 0.030); however, scores on Subscale 1 (p = 0.006) and Subscale 5 (p = 0.004) were significantly elevated in surgical postmenopausal compared to perimenopausal women. Compared to natural postmenopausal women, surgical postmenopausal women had a total BADDS score that was 7.57 points higher (p < 0.001), as well as significantly higher scores on each subscale except for Subscale 4.
Overall, surgical postmenopausal women self-reported the most difficulties with executive functioning followed by perimenopausal women, as can be observed in Figure 2 and Table 6.
| Marginal mean (SE) | Pre | Peri | Natural Post | Surgical Post |
|---|---|---|---|---|
| BADDS total score | 43.7 (1.7) | 54.9 (1.6) | 51.9 (1.5) | 59.5 (1.7) |
| Subscale 1 | 11.4 (0.4) | 13.8 (0.4) | 13.4 (0.4) | 15.3 (0.4) |
| Subscale 2 | 10.8 (0.4) | 13.5 (0.4) | 12.8 (0.4) | 14.8 (0.4) |
| Subscale 3 | 9.0 (0.4) | 11.3 (0.4) | 10.2 (0.4) | 11.8 (0.4) |
| Subscale 4 | 6.9 (0.3) | 9.0 (0.3) | 8.4 (0.3) | 9.2 (0.3) |
| Subscale 5 | 5.5 (0.3) | 7.4 (0.3) | 7.1 (0.3) | 8.4 (0.3) |
Model #2: controlling for age, education, ADHD, difficulty sleeping, anxiety, and depression.
Model #2 examined the effect of menopause group on BADDS scores, adjusting for age, education, ADHD, difficulty sleeping, anxiety, and depression (F10,1900 = 160.80, p < 0.001, adjusted R2 = 0.46). Model #2 was a significantly better fit for the data than Model #1 as indicated by an ANOVA comparison between the two models for total BADDS scores (F3,1900 = 374.79, p < 0.001). Each of the additional covariates in Model #2 had a significant effect on total BADDS scores (difficulty sleeping: β=7.40, p < 0.001; anxiety: β = 15.27, p < 0.001; depression: β=24.04, p< 0.001).
As with Model #1, menopause group significantly impacted total BADDS score (F3,1900 = 43.50, p < 0.001), as well as scores on each of the subscales (Subscale 1 [organizing and activating to work]: F3,1900= 34.72, p < 0.001; Subscale 2 [sustaining attention and concentration]: F3,1900 = 30.71, p < 0.001; Subscale 3 [sustaining energy and effort]: F3,1900 = 35.15, p < 0.001; Subscale 4 [managing affective interference]: F3,1900 = 33.06, p < 0.001; Subscale 5 [utilizing working memory and accessing recall]: F3,1900=27.19, p < 0.001).
Pairwise comparisons between groups for Model #2 are presented in Table 7 (Bonferroni corrected at α= 0.0083). As with Model #1, perimenopausal women had significantly elevated total BADDS scores relative to premenopausal women (5.11 points, p < 0.001). However, Subscales 1 and 3 were no longer significantly different between these groups. In contrast to Model #1, natural postmenopausal women no longer showed any significant differences in total BADDS score or subscale scores relative to premenopausal women. As with Model #1, no significant differences in BADDS scores emerged between perimenopausal and natural postmenopausal women.
| Comparison → | Peri – pre | Natural post – pre | Natural post – peri | |||
|---|---|---|---|---|---|---|
| Outcome ↓ | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value |
| BADDS total score | 5.11 (2.04, 8.18) | 0.001 | 2.95 (—0.81, 6.71) | 0.124 | —2.16 (—5.40, 1.07) | 0.190 |
| Subscale 1 | 0.87 (0.04, 1.70) | 0.040 | 0.68 (—0.34, 1.70) | 0.190 | —0.19 (—1.06, 0.69) | 0.672 |
| Subscale 2 | 1.30 (0.41, 2.18) | 0.004 | 0.84 (—0.24, 1.92) | 0.129 | —0.46 (—1.39, 0.47) | 0.334 |
| Subscale 3 | 1.00 (0.24, 1.75) | 0.010 | 0.15 (—0.78, 1.07) | 0.757 | —0.85 (—1.65, —0.06) | 0.036 |
| Subscale 4 | 0.89 (0.32, 1.47) | 0.002 | 0.41 (—0.30, 1.12) | 0.255 | —0.48 (—1.09, 0.13) | 0.120 |
| Subscale 5 | 1.06 (0.45, 1.66) | <0.001 | 0.87 (0.14, 1.61) | 0.020 | —0.18 (—0.82, 0.45) | 0.572 |
| Comparison → | Surgical post – pre | Surgical post – peri | Surgical post – natural post | |||
|---|---|---|---|---|---|---|
| Outcome ↓ | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value | Mean difference (95 % CI) | p value |
| BADDS total score | 7.65 (4.07, 11.22) | <0.001 | 2.53 (—0.79, 5.86) | 0.135 | 4.70 (1.85, 7.55) | 0.001 |
| Subscale 1 | 1.90 (0.94, 2.87) | <0.001 | 1.03 (0.14, 1.93) | 0.024 | 1.22 (0.45, 1.99) | 0.002 |
| Subscale 2 | 2.18 (1.15, 3.21) | <0.001 | 0.88 (—0.07, 1.84) | 0.070 | 1.34 (0.52, 2.16) | 0.001 |
| Subscale 3 | 1.06 (0.18, 1.94) | 0.018 | 0.06 (—0.75, 0.88) | 0.883 | 0.91 (0.21, 1.61) | 0.011 |
| Subscale 4 | 0.63 (—0.04, 1.30) | 0.065 | —0.26 (—0.88, 0.36) | 0.413 | 0.22 (—0.31, 0.76) | 0.418 |
| Subscale 5 | 1.87 (1.17, 2.57) | <0.001 | 0.82 (0.17, 1.47) | 0.014 | 1.00 (0.44, 1.56) | <0.001 |
Differences were calculated based on estimated marginal means controlling for age, education, ADHD, difficulty sleeping, anxiety, and depression. Significance was adjusted for multiple comparisons at α = 0.0083 using the Bonferroni correction. Effects in italics are those that are no longer significant compared to Model #1, which controlled for only age and education. Bolded effects indicate p < 0.0083.
Like Model #1, women who underwent surgical menopause still had a significantly elevated total BADDS score compared to premenopausal women (7.65 points, p < 0.001). However, in contrast to Model #1, Subscales 3 and 4 were no longer significantly different between these groups. No significant differences emerged between surgical postmenopausal and perimenopausal women in Model #2. Surgical postmenopausal women had total BADDS scores that were 4.70 points higher than natural postmenopausal women (p= 0.001); all subscales except for Subscales 3 and 4 were also significantly higher.
Overall, surgical postmenopausal women again self-report the most difficulties with executive functioning, followed by perimenopausal women as can be observed in Figure 3 and Table 8.
| Marginal mean (SE) | Pre | Peri | Natural post | Surgical post |
|---|---|---|---|---|
| BADDS total score | 53.8 (1.4) | 58.9 (1.3) | 56.7 (1.3) | 61.4 (1.4) |
| Subscale 1 | 13.9 (0.4) | 14.7 (0.4) | 14.5 (0.3) | 15.8 (0.4) |
| Subscale 2 | 12.9 (0.4) | 14.2 (0.4) | 13.7 (0.4) | 15.1 (0.4) |
| Subscale 3 | 11.2 (0.3) | 12.2 (0.3) | 11.3 (0.3) | 12.3 (0.3) |
| Subscale 4 | 9.1 (0.3) | 10.0 (0.3) | 9.5 (0.2) | 9.7 (0.3) |
| Subscale 5 | 6.7 (0.3) | 7.8 (0.3) | 7.6 (0.2) | 8.6 (0.3) |
Adjusting for varying ranges in BADDS subscales
In our analyses of the effects of menopause stage and type on BADDS scores, we also wanted to investigate whether menopause stage and type differentially affected specific domains of executive functioning measured by the BADDS subscales (Table 3). Based on the pairwise comparisons between groups in Model #1 (Table 5) and in Model #2 (Table 7), no clear differences between menopause groups emerged on the subscales. Since the BADDS subscales had different ranges, we also analyzed raw subscale scores as percentages of the maximum subscale score to correct for differences in ranges between the subscales. The percentage transformation revealed that scores for all menopause groups were highest on Subscale 1 (organizing and activating to work), followed closely by Subscale 2 (sustaining attention and concentration) (Table S1 in the online supplement), further indicating that menopause stage and type does not appear to differentially impact the domains of executive functioning measured by the subscales.
Discussion
To our knowledge, this is the first study to examine executive dysfunction across the menopause transition while considering the potential confounding effects of both postmenopause type and psychological symptoms. Although postmenopause type (natural vs. surgical) and symptoms such as difficulty sleeping, anxiety, and depression are all factors that are known to impact PFC-dependent executive functions, these factors had not been considered conjointly within the same study prior to our investigation. The main conclusions from this research are twofold. First, this study supports the premise that natural and surgical postmenopause are distinct experiences when it comes to difficulties with executive functioning domains of cognition. In statistical models with and without potential confounders, surgical postmenopausal women had BADDS scores that were significantly higher than both premenopausal and natural postmenopausal women. These findings indicate that surgical postmenopause is associated with heightened subjective executive dysfunction. All analyses controlled for age at the time of the study, so these findings are not confounded by surgical postmenopausal participants being younger on average than natural postmenopausal participants (54.2 vs. 59.0 years). Notably, the BADDS scores of surgical postmenopausal women were not significantly different from those of perimenopausal women in either model, suggesting that executive dysfunction is similar between these groups. Second, psychological symptoms – such as sleep disruption, anxiety, and depression – are critical confounders of the relationship between the menopause transition and executive dysfunction that need to be considered. Specifically, when these variables were added as covariates in our model, BADDS scores in natural postmenopausal women no longer significantly differed from premenopausal women, indicating that, in women who undergo menopause naturally, self-reported executive dysfunction does seem to improve after the perimenopause peak in executive function difficulties. However, BADDS scores in natural postmenopausal women were not significantly lower than in perimenopausal women, who still had higher BADDS scores than premenopausal women, suggesting that this recovery in natural postmenopause is only partial. Together, these findings support the conclusion that executive functioning after perimenopause may partially recover to premenopausal levels, but only for natural postmenopausal women and only when accounting for the confounding effects of important psychological symptoms – namely, difficulty sleeping, anxiety, and depression.
In this study, cancer and chemotherapy history did not explain why surgical postmenopausal women report worse executive dysfunction, as these variables were not significantly associated with BADDS scores in models adjusted for age, education, and ADHD. This finding emphasizes the relevance of the psychological covariates we considered (difficulty sleeping, depression, and anxiety). The absence of an effect of chemotherapy on BADDS is consistent with past research that found a history of chemotherapy did not impact BADDS scores among women with BRCA1 or BRCA2 germline mutations who had undergone risk-reducing salpingo-oophorectomy [24]. However, the prevalence of chemotherapy was low among participants in the present study (Table 2), possibly limiting our ability to detect an association with BADDS scores. Although cancer and chemotherapy history are still important to consider when investigating cognitive impairment in surgical postmenopausal women, studies on cancer-related cognitive impairment have largely disagreed on the extent to which cancer and chemotherapy impair cognition and which domains of performance are most affected and for how long [18]. The lack of a significant effect of cancer or chemotherapy on BADDS scores emphasizes the importance of difficulty sleeping and clinically significant levels of anxiety and/or depression on executive dysfunction. Interestingly, the prevalence of these confounders was highest among surgical postmenopausal women and perimenopausal women, further highlighting the similarities between these two groups.
Although the psychological symptoms examined in this study are clearly relevant to executive function across the menopause transition, it is not possible to determine whether the relationship is causal and, if so, the direction of that causality. For example, hormonal changes associated with the menopause transition increase sleep difficulties and symptoms of anxiety and depression, which may then impair executive function [23,27,42]. Alternatively, or additionally, the menopause transition may increase executive dysfunction, leading to difficulty sleeping and depression and anxiety symptoms due to stress and reduced quality of life stemming from cognitive difficulties [4]. Difficulty sleeping and anxiety and depression symptoms may also have independent effects on, or be independently affected by, executive dysfunction. Future studies designed to test for mediation effects are necessary to disentangle the causal relationship between psychological symptoms and executive function during the menopause transition, which may be bidirectional. Future research should also consider more detailed measures of the psychological variables examined in this study, as well as others not investigated here. For example, using a validated metric for sleep like the Pittsburgh Sleep Quality Index [43] would allow for an investigation into how the frequency, severity, and nature of sleep difficulties are associated with executive functioning difficulties. Vasomotor symptoms, such as hot flashes, are also common during the menopause transition and are associated with greater self-reported struggles with cognitive function [4].
Despite the important contributions of this study for understanding the role of potential confounders in the relationship between cognition and menopause, four main limitations are critical to consider. First, all measures were assessed via self-reports, which are more susceptible to participant biases than objective measures. While the BADDS has been used to accurately assess severity of ADHD symptoms and efficacy of ADHD medications in clinical trials [44,45], previous research has shown that perceptions of cognitive function do not reliably map onto concurrent measures of cognitive task performance [46,47]. However, the BADDS has the advantage of being able to gauge perceptions about multiple domains of executive functioning quickly within the same instrument, including ability to initiate engagement with a task, maintain focus on the task, regulate emotions that may interfere with focus, and utilize working memory to sustain performance [44,45]. By contrast, objective tests of cognitive performance are time consuming and limited to measuring a specific domain of cognition. Utilizing the BADDS allowed us to observe that menopause stage and type did not clearly relate to perceived deficits on particular subdomains of executive functioning over others but rather was more important for perceptions of global executive functioning (total BADDS scores). Furthermore, subjective reports of cognitive difficulty are relevant to perceived quality of life [45] and have been shown to predict future declines in objective measures of cognitive performance [48]. Self-reports of cognition are therefore important to consider in research and clinical practice, as they are highly relevant to menopausal women’s quality of life in real-world contexts, such as in the workplace.
The second limitation is that we sampled participants cross-sectionally rather than longitudinally, meaning that we compared groups of participants in different stages and types of menopause rather than measuring changes in executive functioning within the same participants across the menopause transition. Longitudinal studies have greater power to detect cognitive changes over time by accounting for individual differences in cognitive baselines and variation in the rate of change [49,50]. However, using a cross-sectional design and measuring executive function via self-report also offered several advantages. First, it allowed us to achieve a large sample size within each menopause group, including surgical postmenopausal participants, who are often underrepresented in research on the menopause transition [51,52]. Additionally, we were able to avoid repeated cognitive testing over time, which can lead to performance increases due to practice, making it more difficult to isolate the effect of age as well as menopause stage and type on cognitive function [53]. Nevertheless, a longitudinal study would be necessary to confirm our findings from this cross-sectional study of executive function difficulties.
The third limitation is that this study was not equipped to examine the impact of hormone therapy (HT) use on executive function. A thorough analysis of the effects of HT need to include details such as type of HT, when HT was initiated, and duration of use, both according to chronological age and relative to menopausal stage and type. These details about HT were not possible to ascertain in this cross-sectional survey study. However, HT during the menopause transition is important to consider given previous findings that hormonal birth control [54,55] and HT [8,56] may impact cognitive function. However, the directionality of HT effects on cognition are complex as HT during menopause can be either beneficial or detrimental depending on the cognitive domain examined [17] and/or the timing and duration of HT use [20,56–58]. For instance, estrogen therapy may benefit cognition if started during perimenopause but not postmenopause, though results are inconclusive [14,15,56]. For surgical postmenopausal women, estrogen therapy benefits cognition if initiated prior to approximately age 50, but the efficacy declines with age [56]. However, estrogen is contraindicated for some postmenopausal women, such as those at high risk for breast cancer [59]. More research into the use of HT for cognition in postmenopausal women, including the timing of treatment (according to chronological and reproductive age) and the associated risks vs. benefits, is needed. Given the complexity of the relationship between the menopause transition and executive function, it will be important in future studies, especially longitudinal ones, to evaluate the impact of HT.
Lastly, the fourth limitation is that the findings from this study primarily come from White, educated, English-speaking women who had access to the internet to complete the online questionnaires. Experiences and symptoms during the menopause transition can vary in different countries [60] and depend on social and cultural factors [61–63]. Future investigations should consider postmenopause type (natural vs. surgical) and psychological symptoms in a broader, cross-cultural sample of participants.
Conclusions
Collectively, this research supports the conclusion that natural and surgical postmenopause need to be considered as distinct experiences and that difficulties with executive functioning are heightened in surgical postmenopause. Psychological symptoms, including difficulty sleeping, depression, and anxiety, also need to be considered as potential confounders in the relationship between executive dysfunction and the menopause transition, specifically whether executive functioning difficulties persist in postmenopause. Without accounting for psychological symptoms, natural postmenopausal women have increased difficulties with executive functioning similar to perimenopausal women. However, when accounting for difficulty sleeping, depression, and anxiety, natural postmenopausal women show executive function difficulties that are partially improved to premenopausal levels. The relevance of psychological symptoms and postmenopause type to perceived executive dysfunction will be important for researchers and clinicians to consider in the context of health-related quality of life for menopausal women.
Footnotes
Contributors: Chloe E. Page participated in conducting and interpreting statistical tests and drafting and editing of the paper. Brianna Soreth participated in study conception, design, data collection and management, and manuscript preparation. Christina A. Metcalf participated in study conception, design, and substantive revisions of the paper. Rachel L. Johnson participated in conducting and interpreting statistical analyses. Korrina A. Duffy participated in selection and interpretation of statistical analyses and substantive revisions of the paper. Mary D. Sammel participated in selecting, conducting, and interpreting statistical analyses. James Loughead participated in study conception and design and manuscript preparation. C. Neill Epperson participated in study conception, design, and substantive revisions of the paper. All authors saw and approved the final version and no other person made a substantial contribution to the paper.
Funding: This work was funded by National Cancer Institute (NCI), United States grant R01 CA215587 to C. Neill Epperson, James Loughead, Brianna Soreth, Mary D. Sammel, and Rachel L. Johnson.
Ethical approval: These experiments were approved by the University of Pennsylvania and the University of Colorado Anschutz Medical Campus human investigations review boards.
Provenance and peer review: This article was not commissioned and was externally peer reviewed.
Research data (data sharing and collaboration): There are no linked research data sets for this paper. Data will be made available on request.
Appendix A. Supplementary data: Supplementary data to this article can be found online at https://doi.org/10.1016/j.maturitas.2023.01.007.
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Published in print: Winter 2024
Published online: 16 January 2024
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Declaration of competing interest: Dr. Epperson consults for Sage Therapeutics and Asarina Pharma and is an investigator for a multisite clinical trial conducted by Sage Therapeutics. All other authors declare no other conflicts of interest.
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