Abstract
Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without menstrual cycle-related affective symptoms (n=15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability (n=21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate (q<0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO4 (q=0.166 and q=0.001, respectively)) and after treatment with P4 (that is, allopregnanolone (q=0.001 for both PMDD and controls), pregnanediol (q=0.077 and q=0.030, respectively) and cortexone (q=0.118 and q=0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate (q=0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate (q=0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate (q=0.065) and pregnenolone sulfate (q=0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.
Highlights
Premenstrual dysphoric disorder (PMDD) is a clinically distinct affective disorder characterized by recurrent and distressing mood and behavioral symptoms during the luteal phase of the menstrual cycle that remit within a few days from the onset of menses.[1,2,3]
When ovarian steroid secretion is suppressed by gonadotropin-releasing hormone (GnRH) receptor agonists, women with PMDD experience remission of symptoms, which recur when physiologic doses of E2/P4 are added back
Functional impairment was characterized as a daily rating form (DRF)[38] score of 2 or higher on one of 4 questions related to functional impairment in at least 3 days out of 7 days pre-menses
Summary
Premenstrual dysphoric disorder (PMDD) is a clinically distinct affective disorder characterized by recurrent and distressing mood and behavioral symptoms during the luteal phase of the menstrual cycle that remit within a few days from the onset of menses.[1,2,3] Levels of circulating ovarian steroids, estradiol (E2) and progesterone (P4) and hypothalamic–pituitary–ovarian axis function are normal.[4]. Asymptomatic controls undergoing identical hormone manipulations experience no changes in mood.[5] in women with PMDD, clinical evidence suggests that symptoms are triggered by a differential central nervous system (CNS) response to physiologically normal changes in E2/P4. Imaging studies identified brain regions modulated by E2/P4 (or their neuroactive metabolites), some of which respond differently in women with PMDD despite similar exposures to E2/P4, including the amygdala, striatum, medial orbitofrontal cortex, anterior cingulate cortex and prefrontal cortex.[6,7,8,9,10,11,12,13,14,15] One candidate hormone that could mediate the differential regulation of brain circuitry in PMDD, and the triggering of symptoms by at least progesterone, is the ring A-reduced neurosteroid allopregnanolone. Despite the absence of consistent demonstrations of abnormal peripheral levels of allopregnanolone in PMDD
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