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Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

ABSTRACT: BACKGROUND:The molecular mechanisms underpinning the progesterone-triggering mood symptoms in women with premenstrual dysphoric disorder (PMDD) are unknown. Cell metabolism is a potential source of variability. Very little is known about the effect of progesterone sensitivity on the metabolome. In this study, we aimed to characterize the effects of progesterone on the global metabolic profile and explore the differences between women with PMDD and controls. METHODS:Plasma was obtained from 12 women with prospectively confirmed PMDD and 25 controls under two hormone conditions: (1) gonadal suppression induced by leuprolide acetate (3.75 mg IM monthly) and (2) add-back phase with leuprolide and progesterone (200 mg twice daily by vaginal suppository). The global metabolic profile was obtained using liquid and gas chromatography followed by mass spectrometry. Differences between groups and time points were tested using repeated measures analysis of variance. The false discovery rate was calculated to account for multiple testing. RESULTS:Amino acids and their derivatives represented 78% (28/36) of the known compounds that were found in significantly lower plasma concentrations after progesterone administration than during gonadal suppression. The concentration of tyrosine was nominally significantly decreased after progesterone add-back in controls, but not in cases (P = 0.02). CONCLUSION:Plasma levels of some amino acids are decreased in response to progesterone. Albeit preliminary, evidence further suggests that progesterone has a different effect on the metabolic profiles of women with PMDD compared to controls. Further research is needed to replicate our findings in a larger sample and to identify the unknown compounds, especially those differentially expressed.

SUBMITTER: Di Florio A

PROVIDER: S-EPMC7440927 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

Di Florio Arianna A Alexander Danny D Schmidt Peter J PJ Rubinow David R DR

Depression and anxiety 20180905 12

<h4>Background</h4>The molecular mechanisms underpinning the progesterone-triggering mood symptoms in women with premenstrual dysphoric disorder (PMDD) are unknown. Cell metabolism is a potential source of variability. Very little is known about the effect of progesterone sensitivity on the metabolome. In this study, we aimed to characterize the effects of progesterone on the global metabolic profile and explore the differences between women with PMDD and controls.<h4>Methods</h4>Plasma was obta ...[more]

PMID: 30184299

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Project description:Bipolar disorder (BD) and premenstrual dysphoric disorder (PMDD) are two cyclic mood illnesses, sometimes presenting together. Their comorbidity appears to be linked to common biological mechanisms and usually results in more severity of mood symptoms and a poorer long-term outcome. Nevertheless, the management of comorbid PMDD/BD has been scarcely studied. Therefore, the aim of the present paper was to review the published literature on the treatment of comorbid PMDD/BD and to provide point-by-point hypotheses to address these complex clinical cases. We searched PubMed to identify the studies focused on the treatment and management of comorbid PMDD/BD using the following search words, alone and in combination: premenstrual dysphoric disorder, bipolar disorder, comorbid, treatment, management, pharmacotherapy, psychotherapy. The search was conducted on the 1st of June 2019 and yielded 55 records. Four papers met our inclusion/exclusion criteria and were therefore included in our qualitative synthesis. Integrating the few data pertaining to the treatment of comorbid PMDD/BD with the large amount of published data on the two conditions separately, we can suggest that the management of comorbid PMDD/BD needs as a first step to stabilize the bipolar symptoms by means of optimal dosages of mood stabilizers. Then, in euthymic BD patients, the PMDD symptoms could be treated with estroprogestins (first-line treatment). On the contrary, during acute phases of BD, antidepressants (for major depressive episodes) and atypical antipsychotics/hormonal modulators (for manic episodes) could be considered as promising add-on treatments to mood stabilizers. In case of resistant PMDD/BD symptoms, combined strategies should be taken into account, as well as alternative treatments, such as lifestyle changes. In conclusion, RCTs on comorbid PMDD/BD are still lacking. The management of this complex condition is therefore challenging and it requires a tailored treatment.

Project description: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.

Project description:AimsPremenstrual dysphoric disorder (PMDD) is a psychiatric condition that is associated with the menstrual cycle. Elucidation of the neural regulation mechanisms of brain reactivity to emotional stimuli among women with PMDD may inform PMDD treatment.MethodsEighty-six women (42 PMDD, 44 healthy controls) were allocated into two groups (anger-induced group: 23 PMDD vs. 23 controls; depression-induced group: 19 PMDD vs. 21 controls). During the luteal phases of the menstrual cycle, all the women were subjected to functional magnetic resonance imaging (fMRI). fMRI resting-state scans were performed before and after the study participants had performed an emotional stimuli task. After the emotional stimuli task, emotional status of the participants were evaluated by Self-Rating Depression Scales (SDS) and Trait Anger Expression Inventory-II (STAXI-II). In addition, all the participants were requested to complete the Eysenck Personality Questionnaire (EPQ) and the Twenty-Item Toronto Alexithymia Scale (TAS-20).ResultsCompared to healthy controls, all women with PMDD exhibited significantly high scores in Tas-20 (p<0.001), higher neuroticism and psychoticism scores as well as significantly low extraversion and social desirability scores (p<0.05). Compared to the controls, f-MRI revealed that PMDD women had elevated ReHo in the middle frontal gyrus (BA10), temporal lobe (BA42), left cerebellum (BA37), as well as decreased activation in the precuneus (BA7), superior frontal gyrus (BA8), lobulus paracentralis (BA6), and right cerebellum (BA48) (p<0.05). Moreover, depression stimuli showed that women with PMDD had elevated ReHo levels in the middle frontal gyrus (BA11), the middle gyrus (BA47) and in the cingulate gyrus (BA23) vs. healthy controls (p<0.05).ConclusionsWomen with more neuroticism and psychoticism, less extraversion and social desirability tend to report PMDD symptoms. Women with this condition experience difficulties in regulating emotions during the luteal phase of the menstrual cycle. Abnormal ReHo levels in the precuneus, superior frontal gyrus, lobulus paracentralis, and right cerebellum may contribute to anger dysregulation. Hypoactivation in the middle frontal gyrus, the middle gyrus and the cingulate gyrus may be generally associated with depression dysregulation in PMDD.

Dataset Information

Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

Publications

Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

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