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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
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Reproduktiv hälsa/Sundström Poromaa)
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström Poromaa)
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2013 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 7, 1133-1144 p.Article in journal (Refereed) Published
Abstract [en]


Most women on combined oral contraceptives (COC) report high levels of satisfaction, but 4-10% complain of adverse mood effects. 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. A second aim was to determine if COC use is associated with changes in brain reactivity in regions previously associated with emotion processing.


Thirty-four women with previous experience of mood deterioration during COC use were randomized to one treatment cycle with a levonorgestrel-containing COC or placebo. An emotional face matching task (vs. geometrical shapes) was administered during functional magnetic resonance imaging (fMRI) prior to and during the COC treatment cycle. Throughout the trial, women recorded daily symptom ratings on the Cyclicity Diagnoser (CD) scale.


During the last week of the treatment cycle COC users had higher scores of depressed mood, mood swings, and fatigue than placebo users. COC users also had lower emotion-induced reactivity in the left insula, left middle frontal gyrus, and bilateral inferior frontal gyri as compared to placebo users. In comparison with their pretreatment cycle, the COC group had decreased emotion-induced reactivity in the bilateral inferior frontal gyri, whereas placebo users had decreased reactivity in the right amygdala.


COC use in women who previously had experienced emotional side effects resulted in mood deterioration, and COC use was also accompanied by changes in emotional brain reactivity. These findings are of relevance for the understanding of how combined oral contraceptives may influence mood. Placebo-controlled fMRI studies in COC sensitive women could be of relevance for future testing of adverse mood effects in new oral contraceptives.

Place, publisher, year, edition, pages
2013. Vol. 38, no 7, 1133-1144 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-188504DOI: 10.1016/j.psyneuen.2012.11.006ISI: 000320412400018PubMedID: 23219471OAI: oai:DiVA.org:uu-188504DiVA: diva2:577983
Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2014-03-14Bibliographically approved
In thesis
1. Ovarian Steroid Hormones, Emotion Processing and Mood
Open this publication in new window or tab >>Ovarian Steroid Hormones, Emotion Processing and Mood
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is known that some psychiatric disorders may deteriorate in relation to the menstrual cycle. However, in some conditions, such as premenstrual dysphoric disorder (PMDD), symptomatology is triggered mainly by the variations in ovarian steroid hormones. Although symptoms induced by fluctuations in ovarian steroids often are affective, little is known about how emotion processing in women is influenced by variations, or actual levels, of ovarian steroid hormones.

The general aim of this thesis was to evaluate menstrual cycle effects on reactivity in emotion generating and controlling areas in the corticolimbic system to emotional stimulation and anticipation, in healthy controls and women with PMDD. A second aim was to evaluate corticolimbic reactivity during long-term administration of exogenous ovarian steroids.

In study I, III and IV effects of the menstrual cycle on emotional reactivity in women with PMDD was studied. In study I, women with PMDD in displayed higher amygdala reactivity than healthy controls to emotional faces, not in the luteal phase as was hypothesised, but in the follicular phase. No difference between menstrual cycle phases was obtained in women with PMDD, while healthy controls had an increased reactivity in the luteal phase. The results of study I was further elaborated in study III, where women with PMDD were observed to have an increased anticipatory reactivity to negative emotional stimuli. However, no differences in amygdala reactivity to emotional stimuli were obtained across the menstrual cycle. Finally, in study IV the hypothesis that amygdala reactivity increase in the luteal phase in women with PMDD is linked to social stimuli rather than generally arousing stimuli was suggested, tested and supported.

In study II, re-exposure to COC induced mood symptoms de novo in women with a previous history of COC-induced adverse mood. Women treated with COC reported increased levels of mood symptoms both as compared to before treatment, and as compared to the placebo group. There was a relatively strong correlation between depressive scores before and during treatment. The effects of repeated COC administration on subjective measures and brain function were however dissociated with increased aversive experiences accompanied by reduced reactivity in the insular cortex.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 912
premenstrual dysphoric disorder, menstrual cycle, combined oral contraceptives, estrogen, estradiol, progesterone, ethinyl-estradiol, levonorgestrel, randomized clinical trial, placebo, fMRI, amygdala, ACC, insula, dlPFC, mPFC, IFG, MFG
National Category
Obstetrics, Gynecology and Reproductive Medicine Psychiatry Radiology, Nuclear Medicine and Medical Imaging Psychology (excluding Applied Psychology)
Research subject
Medical Science; Obstetrics and Gynaecology
urn:nbn:se:uu:diva-199791 (URN)978-91-554-8693-8 (ISBN)
Public defence
2013-08-30, Auditorium Minus, Gustavianum, Museum Gustavianum Akademigatan 3, Uppsala, 09:15 (English)
Available from: 2013-06-05 Created: 2013-05-14 Last updated: 2013-08-30Bibliographically approved

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Gingnell, MalinEngman, JonasFrick, AndreasMoby, LenaWikström, JohanFredrikson, MatsSundström Poromaa, Inger
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