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No decrease in perseverance and performance on cognitive tasks in Danish cohort of hormonal contraceptive users

Published online by Cambridge University Press:  16 January 2023

Maria Nissen Byg
Affiliation:
Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
Andrea Dioni
Affiliation:
Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
Michael Winterdahl*
Affiliation:
Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark Department of Nuclear Medicine and PET-Centre, Aarhus University, Aarhus, Denmark
*
Author for correspondence: Michael Winterdahl, Email: [email protected]
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Abstract

Cognitive consequences of hormonal contraceptives (HCs) are largely underexplored, despite the popularity of use. This study investigates the association between perseverance during cognitively challenging tasks and the use of HCs among Danish women. We hypothesised that women using HCs show decreased perseverance across tasks compared to their naturally cycling counterparts. We further hypothesised that HC using women would show decreased performance as a measure of accuracy (i.e. more incorrect answers) compared to naturally cycling women. The study used a cross-sectional repeated measures design, consisting of a Danish version of the Anagram Persistence Task and the Hagen Matrices Test, followed by an extensive survey documenting menstrual and HC history for each participant. The study was conducted online. Data processing was conducted on data from 129 participants. The former hypothesis was analysed through multilevel regression with a nested random effects structure on log-transformed data. The latter hypothesis was analysed through a multilevel generalised linear model with a nested random effects structure using the binomial family. No support was found for either of the hypotheses.

Type
Original Article
Copyright
© The Author(s), 2023. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

Highlights

  • Hormonal contraception does not impair perseverance in cognitively challenging tasks in Danish participants.

  • Hormonal contraception users and naturally cycling women were well matched in demographic and socio-economic measures.

Limitations

  • High dropout rate prior to filling out questionnaire, increasing risk of survivorship bias.

  • No collection of biological markers.

Introduction

For the past half-century, hormonal contraceptives (HCs) have been used by adult and adolescent women all around the world (Brønnick et al., Reference Brønnick, Økland, Graugaard and Brønnick2020). Despite the massive popularity of various forms of HCs, only a relatively sparse amount of research exists on the cognitive implications of usage. Potential cognitive consequences for a plethora of areas are however suggested by a small but growing body of literature and supported by structural and functional changes within the brain of HC users (Brønnick et al., Reference Brønnick, Økland, Graugaard and Brønnick2020). Studies have considered the potential cognitive effects of oral contraceptives (OC) and intrauterine devices (IUD), with several studies combining data from the two groups. Increased risk of depression and altered mood (Garforth et al., Reference Garforth, Degnbol, Terris, Zak and Winterdahl2020, Gingnell et al., Reference Gingnell, Engman, Frick, Moby, Wikström, Fredrikson and Sundström-Poromaa2013; Skovlund et al., Reference Skovlund, Mørch, Kessing and Lidegaard2016) have been observed in both OC and IUD users. Furthermore, changes in verbal and visuospatial abilities have been found in OC users, suggesting improved abilities (Cicinelli et al., Reference Cicinelli, De Tommaso, Cianci, Colacurci, Rella, Loiudice, Cicinelli and Livrea2011; Gogos, Reference Gogos2013; Mordecai et al., Reference Mordecai, Rubin and Maki2008), decreased performance (Griksiene et al., Reference Griksiene, Monciunskaite, Arnatkeviciute and Ruksenas2018; Griksiene & Ruksenas, Reference Griksiene and Ruksenas2011), or no differences between groups (Mordecai et al., Reference Mordecai, Rubin and Maki2008). This conflict in findings is prevalent throughout studies and is suggested to be dependent on whether treatments are androgenic or antiandrogenic (Griksiene & Ruksenas, Reference Griksiene and Ruksenas2011; Wharton et al., Reference Wharton, Hirshman, Merritt, Doyle, Paris and Gleason2008).

The implications of possible alterations in perseverance range widely: Perseverance has been linked to general mental toughness, academic performance, self-control, and cognitive flexibility, amongst other areas (Duckworth et al., Reference Duckworth, Peterson, Matthews and Kelly2007; Gucciardi et al, Reference Gucciardi, Peeling, Ducker and Dawson2016; Kalia et al, Reference Kalia, Fuesting and Cody2019; Duckworth & Seligman, Reference Duckworth and Seligman2005; Marszał-Wiśniewska & Jarczewska-Gerc, Reference Marszał-Wiśniewska and Jarczewska-Gerc2016). Studies specifically investigating the effect of HC use on perseverance are however limited in quantity. A main contributor to the research area suggests that perseverance and performance on cognitively demanding tasks may be negatively correlated with HC use (Bradshaw et al., Reference Bradshaw, Mengelkoch and Hill2020). Put briefly, the study found women currently using HCs to spend significantly less time attempting to solve tasks requiring great cognitive control compared to naturally cycling women. Likewise, decreased performance was observed in the included tasks, with HC using women performing significantly worse than their naturally cycling counterparts.

Cortisol levels are regulated in part by HC use, and women using OCs have been shown to exhibit decreased cortisol spikes in situations of perceived psychological stress (Kirschbaum et al., Reference Kirschbaum, Pirke and Hellhammer1995), in situations of social stress (Bouma et al., Reference Bouma, Riese, Ormel, Verhulst and Oldehinkel2009), and after straining physical exercise (Bonen et al., Reference Bonen, Haynes and Graham1991; Kirschbaum et al., Reference Kirschbaum, Platte, Pirke and Hellhammer1996) compared to their naturally cycling counterparts. Thus, altered stress reactivity provides a possible explanation for altered perseverance and performance in OC users. A single study has investigated stress reactivity in IUD users (Aleknaviciute et al., Reference Aleknaviciute, Tulen, De Rijke, Bouwkamp, Van der Kroeg, Timmermans and Kushner2017). The study found potentiated cortisol reactivity in IUD users yet blunted reactivity for OC users.

In the present study, perseverance will be understood as a trait of behaviour, influenced by both situational and personality-related factors. More concretely, it will be understood similarly to the concept of grit, that is, refusing to quit in the face of failure and mental hardship (Gucciardi et al., Reference Gucciardi, Peeling, Ducker and Dawson2016). We set out to conduct a study of perseverance and performance similar to that of Bradshaw et al. (Reference Bradshaw, Mengelkoch and Hill2020) in a Danish population, expanding upon the tasks, number of trials, and methods used in the experimental procedure. Similar to previous studies, we hypothesise that women using HCs show less perseverance when solving cognitively demanding tasks compared to naturally cycling women. Due to the expected decrease in perseverance as a measure of time spent, we also hypothesise that women using HCs show diminished performance when solving cognitively demanding tasks compared to naturally cycling women.

Materials and methods

Design and participants

We carried out a web-based experiment, consisting of an Anagram Persistence Task (APT), IQ puzzle tasks, and an extensive survey. The experiment was distributed through a combined effort of online networking, community interactions, and word of mouth. The experiment was online for 6 weeks. Volunteers were recruited on the notion that the study would investigate cognitive effects of HCs and menstrual cycles on cognition. The participants were naive to the experimental design as well as to the specific hypotheses of the study prior to participation. Volunteers had to have Danish fluency and were excluded from the final analysis if they indicated one or more of the following: currently pregnant or breastfeeding, having been on HCs for less than 3 months, suffering from attentional deficit disorders or hormonal disorders, age > 40, not biologically female.

Each participant was given explicit instructions regarding the investigation and their participation prior to initiating the experiment. The consent form and survey were run using Qualtrics (2021) (www.qualtrics.com), and the experiment was coded using PsychoPy Builder (Peirce et al., Reference Peirce, Gray, Simpson, MacAskill, Höchenberger, Sogo, Kastman and Lindeløv2019) and was run by synching to Pavlovia (2021) (www.pavlovia.com).

APT

The first task of the study was a self-constructed Danish version of the APT, consisting of both solvable and unsolvable anagrams. Our APT was made up of 13 unique solvable word scrambles, each with one legitimate correct solution (according to the Danish national dictionary), and two unsolvable word scrambles. As no Danish equivalent of the APT exists from previous studies, the words were constructed by the authors using similar methods to that of Eisenberger and Leonard (Reference Eisenberger and Leonard1980). All words were multisyllabic, and more than two letters move away from a solution in order to ensure equal difficulty on the words (Valerjev & Dujmović, Reference Valerjev and Dujmović2020). The word scrambles used were not presented in a randomised order in accordance with the literature. The presence of unsolvable anagrams was not disclosed to participants prior to participation.

Hagen Matrices Test (HMT)

The second task consisted of 8 IQ puzzle tasks from both the short-form and regular HMT (Heydasch, Reference Heydasch2014). All IQ puzzles had eight multiple-choice options, each labelled with letters a–g. Participants answered by pressing the corresponding key on their keyboard.

Survey

Participants were redirected to an extensive survey after completing both tasks. The survey consisted of demographic questions as well as an extensive review of participants’ history with HC use and menstrual cycle. Participants were expected to use approximately 30 min from initiating the experiment to finishing the survey. The survey alone took approximately 10–15 min to finish.

Statistics and preprocessing

All analyses were carried out in the statistical software environment R (Core Team, 2019) by use of the RStudio (Team, 2020) interface. The main packages used for the analyses were tidyverse (Wickham et al., Reference Wickham, Averick, Bryan, Chang, McGowan, François, Grolemund, Hayes, Henry, Hester, Kuhn, Pedersen, Miller, Bache, Müller, Ooms, Robinson, Seidel, Spinu and Yutani2019), lme4 (Bates et al., Reference Bates, Mächler, Bolker and Walker2015), and lmerTest (Kuznetsova et al., Reference Kuznetsova, Brockhoff and Christensen2017).

The approximate phase in the menstrual cycle was coded for participants following their natural cycle based on reports from the extensive questionnaire. This was done using a calculation with the following syntax: Time spent in the current cycle divided by the typical cycle length in days (in per cent). Hereafter, women were placed in their corresponding current cycle phase. The discrimination cut-off was defined from placing the approximate ovulatory phase in the interval of 45–55% through the typical cycle of any one individual.

Outlier replacement was carried out setting a boundary of three standard deviations from the mean. This affected a total of nine individual trials, distributed among five unique participants, of whom both HC users and naturally cycling women were present.

The distribution of the response time data revealed a typical positive skew characteristic of the type of outcome measure. The data were log-transformed in order to approximate normality, allowing for the use of the general linear mixed effects model. The normality of the data subsequent to transformation was assessed through visual plotting in the form of a QQ plot, which yielded sufficient normality. The data for the accuracy outcome measure followed a binomial distribution.

Preliminary tests were run to assess which predictors should be included in the analyses. We settled on prioritising menstrual phase as a predictor. Based on preliminary investigations, it was decided that types of HC, that is, oral contraceptives (OCs) and IUDs, would be pooled together as no systematic variance was found between groups. In doing so, the current study was more comparable to the similar investigation conducted by Bradshaw et al. (Reference Bradshaw, Mengelkoch and Hill2020).

Analyses

The logged response time was set as the outcome of interest as a proxy for perseverance in a general linear mixed effects model. Model selection was carried out using the Akaike information criterion. The model included HC use as a binary grouping variable, controlling for differences based on education level and task type. The latter was included in the random effects structure, in order to account for different slopes in the model based on tasks of different nature. The model met the assumption of approximating normally distributed residuals.

Response Time ∼ 1 + Use of HCs + Education + Task + (1 + Task | Phase of Menstrual Cycle: Participant ID) + (1 | Phase of Menstrual Cycle)

To account for potential differences in response time between groups, a binomial generalised linear mixed effects model with accuracy as outcome measure was run in order to assess whether any differences were found in performance. A similar model composition was chosen to that of the investigation of perseverance. However, due to the relatively high degree of model complexity combined with a transition to the generalised linear mixed effects model, the model could not converge if the complex nested effects structure was included. Because of this, a decision was made to exclude the menstrual cycle phase variable in the accuracy model. More on this decision can be found in the discussion. The model included HC use as a binary grouping variable, controlling for differences based on education level and task type. Once more, task type was included as a random slope in the random effects structure.

Accuracy ∼ 1 + Use of HCs + Education + Task + (1 + Task | Participant ID)

Results

A total of 148 women completed the study of whom 129 qualified for the analyses based on the inclusion criteria of the study. HC users and naturally cycling women were well matched in the proportion of mean age, BMI, sexual activity, sexual orientation, relationship status, and educational level, see Table 1.

Table 1. Comparison of HC users and naturally cycling women

We found no evidence in favour of the hypothesis that women on HCs spend less time on cognitively demanding tasks at β = 0.31, SE = 0.22, t = 1.43, p > .05 compared to their naturally cycling counterparts. While no significant difference was found between the two groups of interest, both task type and educational level significantly modulated perseverance in the experiment. Estimates on time spent across educational level and task, as well as performance, can be found in the supplementary files.

In the model on accuracy, no significant difference between women on HCs and their naturally cycling counterparts was found, at β = 0.06, SE = 0.15, z = 0.42, p > .05 for HC use. Additionally, no significant difference in accuracy was found based on task type or educational level.

Discussion

While a lot of evidence points to the fact that HC use indeed does have a cognitive impact on women, the general quality of the evidence produced is quite poor. A thorough systematic review by Warren et al. (Reference Warren, Gurvich, Worsley and Kulkarni2014) found that at present, ‘evidence is inconclusive, contradictory and limited by methodological inconsistencies’ (Warren et al., Reference Warren, Gurvich, Worsley and Kulkarni2014). In the 22 eligible studies included in the review, the overall mean in sample size was just 24 OC users per study, with several studies having 10 or fewer participants. The issue is additionally pressing in cross-sectional studies, as the lack of sufficient sample sizes gives way to substantial cognitive variation between individuals (Warren et al., Reference Warren, Gurvich, Worsley and Kulkarni2014). Even with the limited knowledge available, further investigating the potential societal, cultural, and individual impact HC use may have on women is of great importance. Most reviews on current research (Brønnick et al., Reference Brønnick, Økland, Graugaard and Brønnick2020; Schaffir et al., Reference Schaffir, Worly and Gur2016; Warren et al., Reference Warren, Gurvich, Worsley and Kulkarni2014) emphasise the need for more replications, well-powered studies, and well-grounded methodology across studies.

We have tested whether use of HCs is associated with decreased perseverance in cognitively challenging tasks in domains of verbal skills and logical reasoning in a Danish cohort. We found no evidence for differences in perseverance across the two tasks for HC using women compared to naturally cycling women in a Danish population. As to be expected, no difference in performance was found either, as the hypothesis of decreased performance was formulated as a presumption based on possible findings in the investigation of perseverance. Of note, estimates consistently point in the opposite direction of the hypotheses for all tasks and levels of education.

Previously conducted research finds that HCs directly affect and modulates the hypothalamic–pituitary–gonadal (HPG) axis responsible for regulating the reproductive system. The HPG axis has been shown to interact with the hypothalamic–pituitary–adrenal (HPA) axis responsible for regulating free cortisol levels, possibly with oestradiol as a significant driver of the interplay (Høgsted et al., Reference Høgsted, Borgsted, Dam, Nasser, Rye Jørgensen, Ozenne, Stenbæk and Frokjaer2021). Additionally, OC users also show an altered cortisol awakening response with a lower morning cortisol peak and a flatter curve throughout the day (Hampson, Reference Hampson2018; Meulenberg et al., Reference Meulenberg, Ross, Swinkels and Benraad1987; Pruessner et al., Reference Pruessner, Hellhammer and Kirschbaum1999). These decreased spikes are consistent with otherwise higher total cortisol levels in OC using women (Hertel et al., Reference Hertel, König, Homuth, Van der Auwera, Wittfeld, Pietzner, Kacprowski, Pfeiffer, Kretschmer, Waldenberger, Kastenmüller, Artati, Suhre, Adamski, Langner, Völker, Völzke, Nauck, Friedrich and Grabe2017), which suggests alterations in the HPA axis of women on OCs similar to that of permanent stress profiles. This interaction between the two axes and the body of evidence showcasing altered cortisol profiles in HC using women supports the likelihood of there being unintended alterations of cognitive nature, specifically in regard to the area of cortisol interplay in everyday life. These alterations may be related to perseverance and performance. Even though our study finds no evidence supporting decreased perseverance in HC using women, we recommend further explorations into cortisol profiles, perseverance, and HC use.

Considering that most studies referenced in the current research were performed in non-Danish cohorts, it is important to consider the possible variation that may exist between a typical Danish sample of participants as opposed to other populations. Data from a national health survey collected between 2015 and 2017 indicates that American women are more inclined to use combined OCs if they are Caucasian, and even more so when in a relationship. Likewise, prevalence of OC use was positively correlated with years of education (Abma & Martinez, Reference Abma and Martinez2017).

No statistical overview links socio-economic status or advanced demographics in Danish women. However, we believe that the current study has accounted for such variation within the sample, for instance by controlling for educational level and having a balanced population in regard to relationship status. It should however be noted that possible cultural and socio-economic variation between our Danish cohort and cohorts from international studies may exist.

Almost 30% of initially recruited participants quit the experiment prematurely, without having been exposed to all of the included tasks. Due to the experimental design, it is not clear how many of the premature quitters were naturally cycling and how many were HC users. It is uncertain if the women who quit did so due to decreased perseverance, sudden time constraints or, technical issues – as such, it is possible that the study suffers from survivorship bias, if HC using women are overrepresented in premature quitters. We suggest for any similar studies that researchers give great thought to the balance between having tasks that are difficult enough to truly test perseverance versus making sure participants do not quit prematurely.

The study does not include any data on relevant biological markers such as hormonal levels. Any study investigating associations between hormones with cognition would benefit from measuring hormone levels at the time of participation for both naturally cycling women and HC using women. Specifically, such measurements would have allowed the study to more precisely accommodate and control for different hormonal modulators of cognitive function.

A strength of the current study is that all OC users were taking androgenic treatments, consequently avoiding that differing masculinising effects would cancel each other out within this group.

Although the study originally planned on using nonparametric modelling, we opted for log-transforming the response time data in order to reduce model complexity, consequently avoiding convergence issues. We however generally recommend incorporating modelling frameworks true to the underlying distribution of the original data wherever possible.

In line with convergence issues, it did not prove possible to run a model with the same syntax for accuracy (performance) as for response time (perseverance) in the analyses. Forced to leave out the nested effects of different menstrual cycle phases, the model on performance did not take full account of possible trends in the accuracy data for naturally cycling women.

By having time on HCs be an ordinal variable in the current study rather than a continuous measure, much complexity is introduced. With this comes a risk of not accounting for the overall trend in the data, and instead fragmenting the inference.

Despite limitations, this study serves as an important contribution to the field of research regarding the cognitive effects of HC use, meeting the general demand for additional studies on the effects of HCs ranging from molecular to behavioural levels (Pletzer & Kerschbaum, Reference Pletzer and Kerschbaum2014). There are however several issues in the field that should be addressed. Insufficient sample sizes and lack of power are a threat to the legitimacy of results found by studies, in part due to the individual variation it might introduce. It was a priority in the current study to obtain a large sample size, and we encourage future research to similarly make a strong effort to reach adequate power. Studies conducted on participants using different HCs should however consider evaluating potential differences separately.

In general, future studies should seek to further improve on methodology and experimental design, while simultaneously allowing for meaningful comparisons to previously conducted research.

Research in the field should furthermore focus on using consistent and validated cognitive test batteries going forward. At the very least, researchers should strive to be transparent in their reasoning and construction of test batteries if they are not validated and widely accepted tests. Likewise, researchers should make sure to collect adequate information about potential confounding variables, such as age, education, and physical or psychiatric comorbidities (Warren et al., Reference Warren, Gurvich, Worsley and Kulkarni2014).

Conclusion

Despite the popularity of use, the possible cognitive consequences of HCs are largely underexplored. In this paper, we set out to contribute to the still-growing body of research dealing with the topic. The study sought to investigate the possible association between HC use and decrements in perseverance and performance in cognitively demanding tasks among Danish-speaking females. The experiment was conducted online, and data were analysed on a total of 129 participants. No evidence was found in favour of the hypotheses, thus adding to the disagreeing body of literature on the subject of cognitive implications from HCs. Future studies should make efforts to include the time aspect of HC use into their investigations.

Supplementary material

To view supplementary material for this article, please visit https://doi.org/10.1017/neu.2023.7

Data availability statement

The data that support the findings of this study are available on request from the corresponding author.

Acknowledgements

We thank Marie Vadstrup Pedersen for her assistance and feedback.

Financial support

None.

Conflict of interest

None.

Footnotes

Maria Nissen Byg and Andrea Dioni shared first authorship.

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Table 1. Comparison of HC users and naturally cycling women

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