Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill—A double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive
Introduction
Most women on combined oral contraceptives (COC) are satisfied with their contraceptive method (Skouby, 2010). However, 4–10% of COC users experience mood side effects, which typically include depressive symptoms, irritability, and mood swings (Ernst et al., 2002, Kelly et al., 2010). Mood-related side effects are a major reason for discontinuing COC use (Lindh et al., 2009), and in doing so, women turn to less safe contraceptive alternatives (Skouby, 2010), thus increasing their risk of unplanned pregnancies (Segebladh et al., 2009).
To improve tolerability (and safety) of COCs, new progestagens have been developed over the years. Indeed, COCs with anti-androgenic progestagens such as drospirenone and desogestrel appear more favorable in terms of mood symptoms than progestagens with a more androgenic profile such as levonorgestrel (Poromaa and Segebladh, 2012). However, even though COCs have been available for more than 50 years, surprisingly little is known about the underlying biological mechanisms involved in the mood and affect changes that some women experience. Previous depression predisposes to COC-induced mood deterioration (Joffe et al., 2003), but until relevant placebo-controlled trials have been performed, drug-related causality cannot be established. Thus far, three placebo-controlled COC trials have been performed in healthy women, but as these studies only included sterilized women or dysmenorrhea patients, the results may not be valid for typical users (Leeton et al., 1978, Graham et al., 1995, O’Connell et al., 2007). Cross-sectional studies of COC users have indicated that they have increased cortisol levels (Maes et al., 1992, Ansseau et al., 1993), reduced cortisol responsivity (Kirschbaum et al., 1995, Bouma et al., 2009) and lower levels of neurosteroids (Paoletti et al., 2004, Rapkin et al., 2006). Peripheral markers of the serotonin system also appear to be altered in COC users (Weizman et al., 1988, Maes et al., 1992), although a recent PET study found no difference in cortical 5HT2A binding between COC users and non-users (Frokjaer et al., 2009). Finally, we have previously reported that women who experience adverse mood while on COC have deficient prepulse inhibition, a measure of sensorimotor gating with relevance for many anxiety disorders (Braff et al., 2001), in comparison with COC users who reported unchanged emotional well-being (Borgstrom et al., 2008). To date, no studies using functional magnetic resonance imaging (fMRI) have been performed in COC users, why potential emotion-induced brain reactivity effects of COCs remain unexplored.
Stimulus-induced emotional processing typically involves activation of the amygdala, anterior cingulate cortex (ACC) and insula, forming a hypothesized emotion-processing network (Davidson et al., 2000). In addition to these regions, areas in the ventromedial and orbitofrontal cortex have been proposed to have important roles for emotion processing (Fusar-Poli et al., 2009, Pessoa and Adolphs, 2010, Diekhof et al., 2011, Etkin et al., 2011). Of importance for the context of the present study, all of these regions are responsive to ovarian hormones changes or treatments (Amin et al., 2006, Dreher et al., 2007, Andreano and Cahill, 2010, van Wingen et al., 2011, Gingnell et al., 2012, Shafir et al., 2012). Generally, hormonal variations in estradiol and progesterone seem to have opposing effects on reactivity in areas generating and controlling emotions (van Wingen et al., 2011) but findings are not uniform. For example, luteal phase amygdala reactivity has been reported to be both increased (Gingnell et al., 2012, Ossewaarde et al., 2010, Andreano and Cahill, 2010) and decreased (Goldstein et al., 2005, Dreher et al., 2007). Similar diverging patterns have also been observed in the insula and ACC (Shafir et al., 2012, Amin et al., 2006, Frank et al., 2010, Dreher et al., 2007).
Hence, the aim of this randomized, double-blinded, placebo-controlled trial was to investigate if COC use would induce more pronounced mood symptoms than placebo in women with previous history of COC-induced adverse mood. Secondly, we aimed to determine if COC use is associated with changes in brain reactivity in regions previously associated with emotion processing and responsivity to ovarian steroid hormones. In order to enhance the likelihood of detecting differences between placebo and COC users, we exposed the women to a levonorgestrel-containing COC.
We hypothesized that COC use in these susceptible women would be associated with increased reporting of mood symptoms, together with increased amygdala, insula and anterior cingulate cortex reactivity. In addition, we wanted to explore if COC use would alter brain activity in cortical areas, such as the middle and inferior frontal gyri, previously known to be related to emotion processing as well as ovarian hormones.
Section snippets
Participants
The study was carried out at the Department of Obstetrics and Gynecology at Uppsala University Hospital between January 1, 2010 and June 30, 2011. Healthy women (18–45 years), with regular menstrual cycles (25–31 days) and subjective reports of mood deterioration during previous COC use were included if they did not meet any of the exclusion criteria and accepted to use back-up contraception during the study period. Presence of previous COC-induced negative mood was determined by a
Results
Forty women were screened for the study. Of these, four did not fulfill inclusion and exclusion criteria and one subject dropped out prior to randomization. Hence 35 women were randomized to COC or placebo. One woman dropped out of the study immediately after randomization leaving 34 participants in the study. In addition, the scans of two women in the placebo group (pretreatment) and two women in the COC group (one at both sessions and one at pretreatment) were later excluded from the fMRI
Discussion
The major findings of the present study were that women with subjective reports of previous COC-induced mood deterioration displayed depressive mood and mood swings when re-exposed to COC. COC users also had higher scores of depressed mood and mood swings in comparison with placebo users and these COC-induced mood symptom changes were accompanied by altered reactivity in the emotion circuit of the brain especially in the right amygdala and left insula.
Even though 4–10% of COC users complain of
Contributions
M. Gingnell, J. Wikstrom, M. Fredrikson and I. Sundstrom-Poromaa designed the study. M. Gingnell, J. Engman and L. Moby performed data collection. M. Gingnell, J. Engman, A. Frick, M. Fredrikson and I. Sundstrom-Poromaa undertook the statistical analyses. All authors contributed to and have approved the final manuscript.
Role of the funding source
The Swedish Research Council project K2008-54X-200642-01-3, the Swedish Council for Working Life and Social Research projects 2007-1955, and 2007-2116 and the Family Planning Foundation. This study was also partially supported by an unrestricted research grant from Bayer AB, but the authors are alone responsible for the content and writing of the manuscript.
Conflicts of interest
I. Sundstrom-Poromaa serve occasionally on advisory boards or act as invited speaker at scientific meetings for MSD, Bayer Health Care, and Lundbeck A/S. None of the other authors have conflicts of interest to report.
Acknowledgements
The Swedish Research Council project K2008-54X-200642-01-3, the Swedish Council for Working Life and Social Research projects 2007-1955, and 2007-2116 and the Family Planning Foundation. This study was also partially supported by an unrestricted research grant from Bayer AB, but the authors are alone responsible for the content and writing of the manuscript.
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