Abstract
Sex-hormone fluctuations may increase risk for developing depressive symptoms and alter emotional processing as supported by observations in menopausal and pre- to postpartum transition. In this double-blinded, placebo-controlled study, we used blood−oxygen level dependent functional magnetic resonance imaging (fMRI) to investigate if sex-steroid hormone manipulation with a gonadotropin-releasing hormone agonist (GnRHa) influences emotional processing. Fifty-six healthy women were investigated twice: at baseline (follicular phase of menstrual cycle) and 16±3 days post intervention. At both sessions, fMRI-scans during exposure to faces expressing fear, anger, happiness or no emotion, depressive symptom scores and estradiol levels were acquired. The fMRI analyses focused on regions of interest for emotional processing. As expected, GnRHa initially increased and subsequently reduced estradiol to menopausal levels, which was accompanied by an increase in subclinical depressive symptoms relative to placebo. Women who displayed larger GnRHa-induced increase in depressive symptoms had a larger increase in both negative and positive emotion-elicited activity in the anterior insula. When considering the post-GnRHa scan only, depressive responses were associated with emotion-elicited activity in the anterior insula and amygdala. The effect on regional activity in anterior insula was not associated with the estradiol net decline, only by the GnRHa-induced changes in mood. Our data implicate enhanced insula recruitment during emotional processing in the emergence of depressive symptoms following sex-hormone fluctuations. This may correspond to the emotional hypersensitivity frequently experienced by women postpartum.
Highlights
Mood disorders are among the most common causes for disability and constitute a major and severe public health problem.[1]
Postpartum depression, premenstrual dysphoric disorder (PMDD) and major depression with onset in the menopausal transition phase are examples of mood disorders coinciding with fluctuations, or a rapid decline, in sex-steroid hormone levels
In line with results from previous studies,[24,25] there was no significant test − retest correlation for amygdala activity in the placebo group for any of the contrasts of interest. This was the case for insula activity. Because of this lack of significant test − retest correlation, and because of previous findings of absolute levels of estradiol being of less importance for mood than changes in levels,[3] we considered it appropriate to test for the main effect of group (GnRHa versus placebo) cross-sectionally at post intervention, as well as for a potential relationship between activity in the post-gonadotropin-releasing hormone agonist (GnRHa) session and estradiol and depressive symptoms changes, that is, not accounting for the baseline functional magnetic resonance imaging (fMRI) measures
Summary
Mood disorders are among the most common causes for disability and constitute a major and severe public health problem.[1] The prevalence is twice as high in women relative to men.[2] Postpartum depression, premenstrual dysphoric disorder (PMDD) and major depression with onset in the menopausal transition phase are examples of mood disorders coinciding with fluctuations, or a rapid decline, in sex-steroid hormone levels The mechanisms underlying these phenomena are not well understood, but may be related to neurobiological effects of changes in ovarian sex steroids, in particular estradiol.[3,4]. We hypothesised that GnRHa would induce changes in depressive symptoms in a manner dependent on estradiol changes and emotion-elicited brain activity
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