Search

Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that atypical neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions, which include (1) luteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; (2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and (3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Rationale: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD., Aims: The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers., Methods: Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity., Results: The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p's>0.05)., Conclusion: Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD., Competing Interests: Declaration of Competing Interest ALM holds a provisional patent on the anti-inflammatory effects of allopregnanolone and related neurosteroids, and has current and previous funding from Sage Therapeutics related to the anti-inflammatory actions of allopregnanolone. LH has consulted for PureTech Health and Flo Health. JLP has research funding from NIMH and Janssen Pharmaceuticals; served as a consultant to SAGE Therapeutics, Biogen, Merck, Brii Biologics, Pure Tech, Dionysus Health, and Flo Health; speaker for employees of Karuna Therapeutics; founder’s stock in Dionysus Health; two patents: “Epigenetic Biomarkers of Postpartum Depression” and “Epigenetic Biomarkers of PMDD and SSRI Response.” LMO reports no conflicts of interest, but has research funding from NIMH and NICHD and receives royalties and editorial fees from APA Publishing, Elsevier, and UpToDate., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Premenstrual dysphoric disorder (PMDD) is characterized by a cyclical symptom course. Previous research provides limited findings on possible menstrual-cycle-related psychological and psychoendocrinological processes in PMDD. By using ambulatory assessment (AA), we aimed to compare mood and cortisol cyclicity in individuals with PMDD and healthy controls (HC), and to assess effects of habitual and momentary repetitive negative thinking (RNT) and present moment awareness (PMA) on mood and cortisol across the cycle in both groups. Individuals with PMDD and HC ( n = 60 each) completed baseline questionnaires on habitual RNT and PMA. Momentary rumination and PMA, positive and negative affect (NA), and saliva-cortisol were assessed over four consecutive days during both the follicular and the late-luteal phase. Individuals with PMDD showed mood cyclicity indicating mood worsening while HC showed cortisol cyclicity indicating decreasing cortisol levels toward the late-luteal phase. In individuals with PMDD, lower habitual RNT and higher habitual PMA predicted better mood only during the follicular phase whereas lower momentary rumination and higher momentary PMA predicted better mood during the late-luteal phase. No effects on cortisol activity were found. In HC, higher habitual PMA predicted lower NA during the late-luteal phase whereas lower momentary rumination and higher momentary PMA predicted stronger cortisol reduction toward the late-luteal phase. While favorable habitual cognitions might not protect individuals with PMDD against premenstrual mood deterioration, respective momentary cognitions may reflect possible protective factors, suggesting an opportunity for microinterventions to directly target late-luteal-phase-specific state processes in affected individuals. The lack of cortisol cyclicity might represent an endocrinological marker for PMDD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The interplay between ovarian hormones, stress, and inflammatory markers in developing premenstrual dysphoric disorder (PMDD) remains inadequately understood. This study investigated the associations of dynamic changes in the levels of estrogen, progesterone, cortisol, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) with PMDD during the luteal phase of the menstrual cycle. A total of 58 women with PMDD and 50 healthy women were recruited in this study. These women's estrogen, progesterone, cortisol, BDNF, and VEGF levels were evaluated during the preovulation (PO), mid-luteal (ML), and late-luteal (LL) phases. Furthermore, the severity of P MDD symptoms, depressive symptoms, perceived stress, inattention, craving for sweet foods, and fatigue was assessed. The findings revealed that women with PMDD with higher levels of progesterone during the ML or LL phase or a greater increase (ML-PO) or higher sum (ML + LL) of luteal progesterone level exhibited a greater increase in PMDD symptoms during the luteal phase than did the healthy controls. Furthermore, women with PMDD exhibited higher cortisol levels during the LL phase than did the controls. The BDNF level was negatively correlated with PMDD severity. Furthermore, BDNF and VEGF levels were negatively correlated with inattention and craving for sweet foods among women with PMDD. These results suggest an association between progesterone and the exacerbation of PMDD symptoms during the LL phase. Women with PMDD have relatively high cortisol levels during the LL phase. Future investigations with experimental designs or larger sample sizes are warranted to verify the roles of progesterone and cortisol in the development of PMDD., Competing Interests: Declaration of competing interest None All authors declare no conflict of interest. This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST106-2314-B-037-040-MY3; MOST109-2314-B-037-083-; MOST110-2314-B-037-066-MY2), Kaohsiung Municipal Ta-Tung Hospital (KMTTH 108-R04; KMTTH-109-R009; KMTTH-110-R004). These institutions have no role in this study's design, process, and publication. This study was not related to any pharmaceutical industries., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Previously, we reported that a reduction in β-Arrestin1 protein levels in peripheral blood mononuclear leukocytes (PBMC) significantly correlated with the severity of depression symptoms in women with premenstrual dysphoric disorder (PMDD). This study aimed to determine whether the reduced premenstrual β-Arrestin1 protein levels were associated with changes in the regulator for late luteal phase progesterone secretion. The study participants ( n = 25) were non-pregnant women between 18 and 42 years of age not taking any antidepressants or receiving therapy and experiencing the luteal phase of menstruation. ELISA determined the β-Arrestin1 protein in PBMC; testosterone and prolactin levels from the plasma were determined by radioimmunoassay. Reduced levels of β-Arrestin1 protein in women with Hamilton Rating Scale for Depression (HAM-D) scores above 19 were observed alongside significantly higher plasma testosterone and prolactin concentrations. Understanding the mechanism underlying the initiation of PMDD will allow for identification of a key perturbed metabolic enzyme that can serve as a target for drug development to ensure the alleviation of PMDD, which has been suggested earlier as a risk factor for developing major depressive disorders.

We established a methodology using machine learning algorithms for determining the pathogenic factors for premenstrual dysphoric disorder (PMDD). PMDD is a disease characterized by emotional and physical symptoms that occurs before menstruation in women of childbearing age. Owing to the diverse manifestations and various pathogenic factors associated with this disease, the diagnosis of PMDD is time-consuming and challenging. In the present study, we aimed to establish a methodology for diagnosing PMDD. Using an unsupervised machine-learning algorithm, we divided pseudopregnant rats into three clusters (C1 to C3), depending on the level of anxiety- and depression-like behaviors. From the results of RNA-seq and subsequent qPCR of the hippocampus in each cluster, we identified 17 key genes for building a PMDD diagnostic model using our original two-step feature selection with supervised machine learning. By inputting the expression levels of these 17 genes into the machine learning classifier, the PMDD symptoms of another group of rats were successfully classified as C1-C3 with an accuracy of 96%, corresponding to the classification by behavior. The present methodology would be applicable for the clinical diagnosis of PMDD using blood samples instead of samples from the hippocampus in the future., Competing Interests: Declaration of competing interest None of the authors have any commercial or financial involvements in connection with this study that represent or appear to represent any conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Premenstrual Dysphoric Disorder (PMDD) is related to an abrupt drop in progesterone and impairments in the HPA axis that cause anxiety. Suffering persons report higher daily-life stress and anxiety proneness that may contribute to developing PMDD, considered a chronic stress-related disorder. Here, we explored the effect of chronic unpredictable stress (CUS) in rats subjected to progesterone withdrawal (PW) and evaluated gene expression of HPA axis activation in the stress-vulnerable Wistar-Kyoto (WKY) rat strain that is prone to anxiety. Ovariectomized WKY rats were randomly assigned to CUS or Standard-housed conditions (SHC) for 30 days. To induce PW, animals received 2 mg/kg of progesterone on day 25th for 5 days; 24 h later, they were tested using the anxiety-like burying behavior test (BBT). After behavioral completion, rats were euthanized, and brains were extracted to measure Crh (PVN) and Nr3c1 (hippocampus) mRNA. Blood corticosterone and vasopressin levels were determined. Results showed that PW exacerbated anxiety-like behaviors through passive coping in CUS-WKY. PW decreased Crh-PVN mRNA and the Nr3c1-hippocampal mRNA expression in SHC. CUS decreased Crh-PVN mRNA compared to SHC, and no further changes were observed by PW or BBT exposure. CUS reduced Nr3c1-hippocampal gene expression compared to SHC animals, and lower Nr3c1 mRNA was detected due to BBT. The PW increased corticosterone in SHC and CUS rats; however, CUS blunted corticosterone when combined with PW+BBT and similarly occurred in vasopressin concentrations. Chronic stress blunts the response of components of the HPA axis regulation when PW and BBT (systemic and psychogenic stressors, respectively) are presented. This response may facilitate less adaptive behaviors through passive coping in stress-vulnerable subjects in a preclinical model of premenstrual anxiety., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

γ-Aminobutyric acid type A receptors (GABAARs) play an important role in cognitive and emotional regulation and are related to the hippocampus. However, little is known regarding patterns of hippocampal GABAAR subunit expression in rat models of premenstrual dysphoric disorder (PMDD). This study investigated the above changes by establishing two PMDD rat models based on Traditional Chinese Medicine (TCM) theories, namely, PMDD liver-qi invasion syndrome (PMDD-LIS) and PMDD liver-qi depression syndrome (PMDD-LDS). Behavioral tests were used to detect depression and irritability emotion. Western blot analysis was used to investigate protein levels of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits, whereas ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis was performed to determine gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the hippocampus across each group. Concurrently, behavioral data indicated that the PMDD-LDS and PMDD-LIS rat models had been successfully established. GABAAR α2, α5, β2, and δ subunit was significantly upregulated, whereas α4 was significantly downregulated (P < 0.05) in PMDD-LDS rat models relative to controls. On the other hand, GABAAR α1, α2, and β3 were significantly downregulated while α4 and β2 were significantly upregulated in PMDD-LIS rat models relative to the control group (P < 0.05). Moreover, GABA levels significantly decreased, while Glu and the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conversely, GABA and Glu levels significantly decreased, whereas the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conclusively, our results revealed differential expression of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits between PMDD-LIS and PMDD-LDS rat models, suggesting that they may be biomarkers in the pathogenesis of PMDD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABA A -modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects 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, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants 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 emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABA A -active neurosteroids., (© 2023. The Author(s).)

GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABA A receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that, in certain individuals, GABA A receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABA A receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA A receptors. The antagonistic effect is noted in most GABA A subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo-induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABA A system., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Premenstrual dysphoric disorder (PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations (CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types, respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology., (Copyright © 2021 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Premenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients' differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca 2+ and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca 2+ homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca 2+ dynamics and ER stress may contribute to the pathophysiology of PMDD., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Premenstrual Dysphoric Disorder (PMDD) is characterized by significant emotional, physical and behavioral distress during the late luteal phase that remits after menses onset. Outlined as a new diagnostic category in DSM-5, the mechanisms underlying PMDD are still insufficiently known. Previous research suggests that PMDD exacerbates with stressful events, indicating a dysregulation of the hypothalamic-pituitary-adrenal axis. However, studies measuring stress-related processes in affected women in real-time and real-life are lacking. We conducted an Ambulatory Assessment (AA) study to compare subjective stress reactivity together with basal and stress-reactive cortisol activity across the menstrual cycle in women with and without PMDD. Women with current PMDD (n = 61) and age- and education matched controls (n = 61) reported momentary mood, rumination, and daily events via smartphones at semi-random time points 8 times a day over two consecutive days per cycle phase (menstrual, follicular, ovulatory, and late luteal). Twenty minutes after assessments participants collected saliva cortisol samples. Three additional morning samples determined the cortisol awakening response (CAR). Women with PMDD reported particular high daily life stress and high arousal negative affect (NA high ) towards stressors during the late luteal phase. High momentary stress levels were linked to lower levels of high arousal positive affect (PA high ) and to higher levels of rumination in PMDD women compared to controls irrespective of cycle phase. Across groups, more stress was linked to higher levels of low arousal NA (NA low ) and to lower levels of low arousal PA (PA low ). Moreover, PMDD was associated with a delayed CAR peak and a flattened diurnal cortisol slope. While neither group showed cortisol reactivity towards daily life stress directly, high momentary NA high and low momentary PA predicted high levels of cortisol across groups, whereas high momentary rumination predicted high cortisol output only in healthy women. In this AA-study we identified important stress-related psychological and endocrinological within-person variability in women with PMDD during daily life. Further research is warranted targeting identified AA-based mechanisms to study their predictive role for the clinical course of PMDD and to provide evidence-based therapeutic options for affected women., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A variety of hormones have been shown to play a role in affective disorders. Reproductive steroids are particularly informative in our efforts to understand the pathophysiology of affective dysregulation for several reasons: i) Reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, perinatal depression, perimenopausal depression) are wonderful clinical models for investigating the mechanisms by which affective state changes occur; ii) Reproductive steroids regulate virtually every system that has been implicated as disturbed in the ontogeny of affective disorders; iii) Despite the absence of a reproductive endocrinopathy a triggering role in the affective disturbance of reproductive mood disorders has been shown clearly for changes in reproductive steroids. The existing data, therefore, support a differential sensitivity to reproductive steroids in reproductive mood disorders such that an abnormal affective state is precipitated by normal changes in reproductive steroids. The therapeutic implications of these findings for affective illness are discussed.

Background: This study evaluated the association between estrogen levels, emotion regulation, depression, anxiety, and stress of women with premenstrual dysphoric disorder (PMDD). We also evaluated the moderating effect of estrogen receptor (ESR) α-Xbal polymorphism on the aforementioned association., Methods: A total of 100 women were diagnosed with PMDD based on psychiatric interviews and a prospective investigation of 3 menstrual cycles. A total of 96 normal individuals were recruited as controls. Their estrogen levels, depression, anxiety, stress, and ESR α-Xbal polymorphism in both premenstrual and follicular phases were assessed, and these data were included in the final analysis., Results: The PMDD group had high depression, anxiety, and stress and low emotional adjusting and tolerating in the premenstrual phase. Emotional adjustment was negatively associated with depression, anxiety and stress. No association was observed between PMDD and estrogen level. However, premenstrual estrogen level was negatively correlated with anxiety and stress in women with PMDD. The association was only significant in G carriers of ESR α-Xbal, as was the difference in premenstrual emotion regulation between the PMDD and control groups., Conclusions: The results demonstrate the association between estrogen and anxiety in PMDD, supporting the claim that women with PMDD differ in their responses to normal estrogen levels. Furthermore, this association and dysfunctional emotional regulation in PMDD existed only among the G carriers of ESR α-Xbal polymorphism. Future studies should investigate the effect of estrogen on brain functions involving emotional regulation in women with PMDD, stratified by ESR α-Xbal polymorphism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA A receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABA A receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P < .005), as well as total DRSP scores (P < .01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA A receptor., (© 2017 British Society for Neuroendocrinology.)

Objective: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective "pacemaker." The authors attempted to determine which condition triggers PMDD symptoms., Method: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed., Results: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ., Conclusions: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

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-SO 4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO 4 (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.

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.

The rise in ovarian hormones triggers premenstrual dysphoric disorder symptoms in women., (Copyright © 2017, American Association for the Advancement of Science.)

We performed an epidemiological investigation of subjects with premenstrual dysphoric disorder (PMDD) to identify the clinical distribution of the major syndromes and symptoms. The pathogenesis of PMDD mainly involves the dysfunction of liver conveyance and dispersion. Excessive liver conveyance and dispersion are associated with liver-qi invasion syndrome, while insufficient liver conveyance and dispersion are expressed as liver-qi depression syndrome. Additionally, a nonconditional logistic regression was performed to analyze the symptomatic features of liver-qi invasion and liver-qi depression. As a result of this analysis, two subtypes of PMDD are proposed, namely, excessive liver conveyance and dispersion (liver-qi invasion syndrome) and insufficient liver conveyance and dispersion (liver-qi depression syndrome). Our findings provide an epidemiological foundation for the clinical diagnosis and treatment of PMDD based on the identification of different types.

Although decades of research has examined the association between cortisol regulation and premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD), no review exists to provide a general set of conclusions from the extant research. In the present review we summarize and interpret research that has tested for associations between PMS/PMDD and cortisol levels and reactivity (n=38 original research articles). Three types of studies are examined: correlational studies, environmental-challenge studies, and pharmacological-challenge studies. Overall, there was very little evidence that women with and without PMS/PMDD demonstrate systematic and predictable mean-level differences in cortisol, or differences in cortisol response/reactivity to challenges. Methodological differences in sample size, the types of symptoms used for diagnosis (physical and psychological vs. only affective), or the type of cortisol measure used (serum vs. salivary), did not account for differences between studies that did and did not find significant effects. Caution is recommended before accepting the conclusion of null effects, and recommendations are made that more rigorous research be conducted, considering symptom-specificity, within-person analyses, and multiple parameters of cortisol regulation, before final conclusions are drawn., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In certain women, increased negative mood relates to the progesterone metabolite, allopregnanolone (allo), during the luteal phase of ovulatory menstrual cycles, the premenstrual dysphoric disorder (PMDD). In anovulatory cycles, no symptom or sex steroid increase occurs but symptoms return during progesterone/allo treatment. Allo is a potent GABAA receptor-modulating steroid and as such is expected to be calming and anxiolytic. A relation to negative mood is unexpected. However, this paradoxical effect can be induced by all GABAA receptor modulators in low concentrations whereas higher concentrations are calming. The severity of the mood symptoms relate to allo in an inverted U-shaped curve at endogenous luteal-phase serum concentrations. Allo's effects on the GABAA receptor can be antagonized by isoallopregnanolone (ISO), an antagonist to allo. ISO has also been used in a preliminary clinical trial on PMDD ameliorating symptoms with good effect in PMDD patients.

Recently designated as a disorder in the DSM-5, premenstrual dysphoric disorder (PMDD) presents an array of avenues for further research. PMDD's profile, characterized by cognitive-affective symptoms during the premenstruum, is unique from that of other affective disorders in its symptoms and cyclicity. Neurosteroids may be a key contributor to PMDD's clinical presentation and etiology, and represent a potential avenue for drug development. This review will present recent literature on potential contributors to PMDD's pathophysiology, including neurosteroids and stress, and explore potential treatment targets.

Objectives: A marked increased in food intake in the late-luteal phase is a characteristic symptom of premenstrual dysphoric disorder (PMDD). The aim of the study was to evaluate the leptin level, caloric intake, and eating behaviors of women with PMDD across the menstrual cycle among normal-weight and overweight subjects, respectively., Methods: A total of 62 women with PMDD and 69 controls were recruited following psychiatric interviewing and underwent prospective investigation. The leptin level, caloric intake, and three factors related to eating behavior were assessed in both the late-luteal and follicular phases., Results: The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the normal-weight women, the leptin level was negatively correlated with caloric intake. The normal-weight women with PMDD had a lower leptin level, a lower leptin/body fat percentage (BFP), a higher caloric intake, and higher uncontrolled eating and emotional eating in the late-luteal phase than the normal-weight controls. Their leptin level was correlated negatively with sweet caloric intake. On the other hand, the overweight women with PMDD had a higher leptin level than the normal-weight women with PMDD and no decline was observed in their leptin level in the late-luteal phase. There were no differences in the leptin level between the overweight women with PMDD and the overweight controls. They also had a higher sweet caloric intake and higher uncontrolled eating and emotional eating than the overweight controls., Conclusions: A decline in the leptin level is associated with late-luteal overeating among normal-weight women with PMDD. Hyperleptinemia and a high sweet caloric intake of overweight women with PMDD should be monitored and addressed in order to attenuate the risk of leptin resistance. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of overeating among women with PMDD should be evaluated in future study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy ((1)H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T (1)H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)