Elsevier

Hormones and Behavior

Volume 126, November 2020, 104849
Hormones and Behavior

Oral contraceptive use, especially during puberty, alters resting state functional connectivity

https://doi.org/10.1016/j.yhbeh.2020.104849Get rights and content

Highlights

  • OC use during puberty increases functional connectivity in the salience network.

  • OC use in general is related to more functional connectivity in the salience, central executive, and reward networks.

  • The higher functional connectivity in OC users provides mechanistic insight for altered cognition and mental health.

Abstract

Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.

Introduction

Oral contraceptives (OCs) have been in the market for over 60 years and are used by millions of women worldwide, making them one of the most widely prescribed medications among women (Pletzer and Kerschbaum, 2014). OCs work by suppressing the hypothalamic-pituitary-gonadal axis through negative feedback, resulting in lower levels of endogenous gonadotropins and ovarian steroid hormones (McGuire et al., 1975). The suppression of these endogenous hormones and the intake of exogenous (i.e., synthetic) hormones via OCs have also been shown to produce negative emotional side effects (Skovlund et al., 2016; Lundin et al., 2017). These side effects may exacerbate women's vulnerability to stress-related mental health disorders by changing brain structure and function (Montoya and Bos, 2017; Lewis et al., 2019). However, the mechanisms mediating this hormone-related vulnerability remain unclear.

Emerging evidence suggests that OC use induces significant structural and functional changes in the brain. Compared to naturally cycling (NC) women, OC users, in their early- to mid-20s, show region-specific increases and decreases in grey matter (GM) volume (Pletzer et al., 2010, Pletzer et al., 2015; Lisofsky et al., 2016; Hertel et al., 2017; Pletzer, 2019; Sharma et al., 2020), white matter (WM) volume and integrity (De Bondt et al., 2013; Sharma et al., 2020) and cortical thickness (Petersen et al., 2015). OC users also generally display several functional differences on tasks that primarily involve memory and emotion, although the direction of the effects appears to be task-dependent. OC users show increased blood‑oxygen-level-dependent (BOLD) response in frontal brain regions (inferior, superior, and middle frontal gyri), as well as in the insula, fusiform gyrus, lingual gyrus, and supplementary motor area when exposed to an emotionally arousing picture n-back task (Sharma et al., 2020). While this heightened BOLD response is consistent with other OC-related functional tasks such as following traumatic film exposure (Miedl et al., 2018), OC users show less BOLD signal in frontal brain regions and in the insula compared to NC women during an emotional face matching task (Gingnell et al., 2013). Thus, OC use alters task-dependent brain activity in areas involved in memory and emotion regulation.

In addition to changes in brain structure and function, other studies have examined resting state functional connectivity (FC) in OC users and NC women. At rest, the brain has a characteristic pattern of synchronous low-frequency oscillations (Biswal et al., 1995, Biswal et al., 1997). A number of functional networks show correlated patterns of activity at rest, with one being the default mode network (DMN). The DMN strongly corresponds to the theory of mind and social cognition tasks (Laird et al., 2011). Other networks, such as the central executive network (CEN) and the salience network (SN), also correspond to specific behavioural outcomes. The CEN is involved in numerous cognitive processes, including reasoning, working memory (e.g., n-back task), and divided attention, whereas the SN is known to link cognition with emotion/interoception (Laird et al., 2011).

Emerging evidence suggests that OCs may alter the resting state FC of various networks in the brain; however, the findings are inconsistent. For example, Petersen et al. (2014) report that OC users show less FC in the angular gyrus of the DMN compared to NC women. In contrast, Pletzer et al. (2016) found more resting state FC in the post-central gyrus of androgenic OC users, but less resting state FC in the superior frontal gyrus of anti-androgenic OC users compared to NC women. While both studies compared OC users to NC women in the follicular phase of the menstrual cycle, Pletzer et al. (2016) also compared users of androgenic OCs separately from users of anti-androgenic OCs. They found that users of anti-androgenic OCs show less resting state FC in the middle prefrontal cortex (mPFC) compared to NC women in the SN (Pletzer et al., 2016). Nevertheless, regardless of pill type, OC users show less resting state FC in the anterior cingulate cortex (ACC) in the SN (Petersen et al., 2014). While Petersen et al. (2014) and Pletzer et al. (2016) both used cross-sectional designs, there is variability in the acquisition of the resting state data between the two studies, which may contribute to inconsistencies in findings (Wang et al., 2015). For example, Pletzer et al. (2016) instructed all participants to keep their eyes closed, whereas Petersen et al. (2014) did not. Furthermore, differences in study designs (e.g., within-subjects compared to between-subjects) can also lead to differences in resting state FC (Engman et al., 2018). In a randomized control trial, women showed greater FC in the ACC of the SN after OC intake compared to before use. Yet, in comparison to placebo users, OC users showed reduced FC between the amygdala and the cuneus and the post-central gyrus (Engman et al., 2018). Overall, these findings show that OCs affect the resting state dynamics across multiple networks, such as the SN and CEN, which are highly implicated in memory and emotion regulation.

While the direction of the effects is mixed due to differences in participant inclusion/exclusion criteria and study design, alterations in FC in these networks have been related to negative affect (Brakowski et al., 2017; Engman et al., 2018), which could exacerbate vulnerability to depression among OC users. The associations between OC use and mood disruptions have received considerable attention in the last few years. OC users show a greater risk of first depression diagnosis and use of psychotropic drugs (e.g., antidepressants, anxiolytics, etc.) than non-OC users (Skovlund et al., 2016; Zettermark et al., 2018). The relative risk of depression and psychotropic drug use is the highest for adolescent OC users who are between 12 and 19 years of age (Skovlund et al., 2016; Zettermark et al., 2018). Additionally, OC users report significantly lower well-being and increased anxiety, irritability, and mood swings in comparison to non-OC users (Bengtsdotter et al., 2018; Lundin et al., 2017; Zethraeus et al., 2017). Finally, OC users display an increased incidence of suicide attempts and suicides compared to non-OC users (Skovlund et al., 2018). While it is unknown whether the duration of OC use is related to the incidence of mood disruptions, the differences between OC users and non-OC users in resting state dynamics may provide a neural mechanism for the increased vulnerability to mood-related disorders following OC use (Engman et al., 2018). However, there is a limited number of studies investigating OC-dependent effects on resting state FC, which warrants further research into the area. The current study aims to contribute to the emerging literature and expand it by incorporating the age of OC onset and duration of use.

The effects of OC use during early adolescence (i.e., puberty) on resting state FC have not been investigated. Puberty is a critical period of development during which gonadal steroid hormones reorganize and remodel the brain (Levitt, 2003; Schulz et al., 2009; Vigil et al., 2016). There is also a high prevalence of psychiatric disorders during this time, namely depression and anxiety (Angold et al., 1998; Shors and Leuner, 2003). Emerging evidence suggests that the pubertal female brain undergoes changes to resting state FC in the DMN and SN that are associated with mood-related symptoms (Ordaz et al., 2016; Ernst et al., 2019). Many women also begin using OCs during puberty for not only reproductive purposes, but for their additional off-label use as “regulators” (e.g., to regulate the menstrual cycle, mood, and skin). The heightened sensitivity of the pubertal/adolescent brain to the organizing effects of circulating gonadal steroid hormones raises concerns about the effects of OC use during this sensitive period. Current literature on OC-related mood symptoms shows that adolescent OC use results in a lasting vulnerability to depression in adulthood (Anderl et al., 2020). Adolescents are also more sensitive than older women to the influence of OCs with regard to first depression diagnosis, suicide attempt, and psychotropic drug use (Skovlund et al., 2016; Skovlund et al., 2018; Zettermark et al., 2018). To date, studies have yet to examine the influence of adolescent OC use on post-adolescent brain function at rest (Cahill, 2018). Additionally, recent findings from our laboratory show that pubertal-onset OC use results in more WM volume in the fusiform gyrus and precuneus and an increased BOLD response in the bilateral lingual gyrus, mid-temporal gyrus, pre-central gyrus, and insula when working memory is engaged compared to OC use in adulthood (Sharma et al., 2020). However, the FC in the DMN, CEN, and emotional networks (i.e., SN, reward network [RN], and subcortical limbic network) at rest remains unknown.

Therefore, the objective of the current study was to examine FC differences in the DMN, CEN, SN, RN, and subcortical limbic network in women who began using OCs either during puberty (i.e., pubertal-onset OC users) or in adulthood (i.e., adult-onset OC users), and in NC women. These networks were determined a priori due to their involvement in memory and emotion regulation. Similarly, based on our previous publication depicting a strong OC-related volumetric difference, we also sought to examine regional FC with the putamen using a seed-to-voxel based approach (Sharma et al., 2020). Based on the OC-related functional differences during an emotional working memory task observed in our previous study (Sharma et al., 2020), we hypothesized that OC users would show more FC in the SN and subcortical limbic network and less FC in the middle, inferior, and superior frontal gyri in the CEN compared to NC women (Engman et al., 2018; Petersen et al., 2014; Pletzer et al., 2016) demonstrating altered emotion regulation and working memory. We also hypothesized that pubertal-onset OC use would result in altered FC compared to shorter OC use during adulthood.

Section snippets

Participants

Women between the ages of 18 and 26 years old were recruited through the University of Ottawa's Integrated System of Participation in Research (ISPR) and in the community. A total of 75 women (mean age 19.6; SD = 1.96) participated in the functional magnetic resonance imaging (fMRI) study. 27 of them were OC users, who self-identified as either pubertal/adolescent-onset or adult-onset users. There were 12 pubertal-onset users and 15 adult-onset users. Pubertal-onset OC users began using OCs

Default mode network (DMN)

The DMN (component 20) showed the strongest correspondence to Laird's ICN13 (Laird et al., 2011), with a high spatial correlation (r = 0.58). It included the precuneus, PCC, middle and anterior cingulate gyri, and parts of the middle and superior frontal gyri. No significant differences in resting state FC were identified in the DMN between OC users and NC women. In addition, a sub-division of the DMN (component 8) was identified with a high spatial correlation with ICN13 (r = 0.44). This

Discussion

In the current study, we used resting state fMRI to investigate OC-dependent changes in FC within various networks. We found that OC use is associated with increased connectivity in predominantly frontal regions of the SN, RN, and CEN. Connectivity in the SN was also dependent on the age of OC onset.

Pubertal-onset OC users showed increased connectivity in the supramarginal gyrus and inferior parietal lobule compared to their adult-onset counterparts. Given that puberty is a period of neuronal

Conclusion

Nonetheless, this study is the first to examine the age-dependent effect of OC use on resting state FC within the DMN, SN, CEN, and RN. This work highlights that pubertal-onset OC use results in higher regional connectivity in the SN compared to shorter OC use during adulthood. In addition, general OC-dependent effects were observed such that OC use is related to greater connectivity in the SN, CEN, RN, and subcortical limbic network and that the CEN and RN may be hot-wired via the dorsolateral

CRediT authorship contribution statement

Rupali Sharma, Andra Smith, and Nafissa Ismail designed the current study. Rupali Sharma was also responsible for data collection, data analysis, and manuscript preparation. Zhuo Fang contributed to data analysis and manuscript preparation. Zhuo Fang, Andra Smith and Nafissa Ismail revised and edited the manuscript.

Funding and acknowledgements

This research was funded by the University of Ottawa Brain and Mind Research Institute and the School of Psychology and Faculty of Social Sciences at the University of Ottawa. We would like to thank the staff at the Brain Imaging Centre for their technical assistance.

Declaration of competing interest

We declare no conflict of interest.

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