Emotional brain activation across the menstrual cycle in women with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

Abstract Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. Allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite, is hypothesized to contribute to the development of PMDD symptoms. On the other hand, the endogenous 3\(\beta\)-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective inhibitory modulation of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotional processing in PMDD, but whether there is some relation to ALLO or ISO is unknown. In the present study, women with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids (estradiol, progesterone) and the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Women with PMDD exhibited greater activity in brain regions which are part of emotion processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotional networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD and control women. Specifically, positive relationships between ISO/ALLO levels and brain activity were found in PMDD women, while the opposite was observed in controls. In conclusion, women with PMDD show altered emotional brain responses in the late-luteal phase of the menstrual cycle which may be related to an altered response to GABAA-active neurosteroids.