A forced swim-based rat model of premenstrual depression: effects of hormonal changes and drug intervention.

Premenstrual dysphoric disorder (PMDD), a form of premenstrual syndrome (PMS), is a severe health disturbance that affects a patient's emotions; it is caused by periodic psychological symptoms, and its pathogenesis remains unclear. As depression-like symptoms are found in a majority of clinical cases, a reliable animal model of premenstrual depression is indispensable to understand the pathogenesis. Herein, we describe a novel rat model of premenstrual depression, based on the forced swimming test, with a regular estrous cycle. The results showed that in the estrous cycle, the depression-like behavior of rats occurred in the non-receptive phase and disappeared in the receptive phase. Following ovariectomy, the depression-like symptoms disappeared and returned after a hormone priming regimen. Moreover, fluoxetine, an anti-depressant, could reverse the behavioral symptoms in these model rats with normal estrous cycle. Further, the model rats showed significant changes in the serum levels of estrogen and progesterone, hippocampal levels of allopregnanolone, 5-hydroxytryptamine, norepinephrine, and γ-aminobutyric acid (GABA), and in the expression of GABAA receptor 4α subunit, all of which were reversed to physiological levels by fluoxetine. Overall, we established a reliable and standardized rat model of premenstrual depression, which may facilitate the elucidation of PMS/PMDD pathogenesis and development of related therapies.

The impact of competitive sports on menstrual cycle and menstrual disorders, including premenstrual syndrome, premenstrual dysphoric disorder and hormonal imbalances.

OBJECTIVES: With the considerable increase of female participation in youth sports, it has become crucial for medical professionals, coaches and parents to improve their competitiveness by understanding the conditions for which these females are at elevated risk and mitigating possible health consequences. The aim of this study was to evaluate the effect competitive sports have on the disorders of the menstrual cycle, to investigate the frequency of PMS (premenstrual syndrome)/PMDD (premenstrual dysphoric order) in professional female athletes and to identify risk factors predisposing for PMS and PMDD. Additionally, the levels of selected hormones such as serum estradiol, FSH, LH and prolactin were investigated to identify any hormonal perturbances that might have influence or be the risk factors for menstrual dysfunctions. MATERIAL AND METHODS: The study group consisted of 75 professional athletes (girls and young women at the age of 16-22) who lived on the territory of Silesia. The control group consisted of 50 girls and young women at the same age, who did not practice any sport. The research tools included daily diary of PMS symptoms created in line with The American College of Obstetricians and Gynecologists (ACOG) recommendations and ICD-10 diagnostic criteria, daily diary of PMDD symptoms created according to DSM-V diagnostic criteria of the American Psychiatric Association (APA) and premenstrual symptoms screening tool (PSST). RESULTS: The analysis of menstrual cycle disorders showed statistical significance for heavy menstrual bleeding (p = 0.01) and longer breaks between menstrual bleeds (p = 0.01). PMDD was diagnosed in 8% and PMS in more than 42% of respondents. The incidence of PMDD was not at significant variance between the groups (9.33% in contrast to 6.0%), while incidence of PMS was statistically different in both groups (p = 0.045) (49.33% vs 32.0%). A significant correlation between PMS, average age (p = 0.00001) and menarche age (p = 0.03) in young active athletes has been shown. The risk of PMS increased with age (by 1.71 with each year) (p = 0.0007). CONCLUSIONS: A number of other risk factors predisposing for PMS and PMDD has also been identified. The findings of these researches will enable the athletic care network to provide better care for young female athletes.

Leptin and ghrelin concentrations and eating behaviors during the early and late luteal phase in women with premenstrual dysphoric disorder.

OBJECTIVES: In this study, we evaluated the changes in leptin and ghrelin concentrations, eating behavior, depression, and impulsivity and their correlations within the luteal phase among women with premenstrual dysphoric disorder (PMDD). METHODS: In 63 women with PMDD and 53 healthy controls, we prospectively evaluated serum levels of leptin and ghrelin, Body Mass Index(BMI), and self-reported sweet cravings, cognitive restraint, uncontrolled eating, emotional eating, depression, and impulsivity during the early luteal (EL) and late luteal (LL) phases. RESULTS: Compared with the controls, the women with PMDD had higher BMI, higher leptin concentrations in the EL and LL phase, and leptin concentrations increased from the EL to the LL phase. However, there is no significant difference in ghrelin. Women with PMDD increased sweet cravings and uncontrolled eating from EL to LL phase. No significant correlation was observed between the EL-LL changes in leptin or ghrelin concentrations and those in eating behaviors. Both depression and impulsivity correlated with sweet craving and uncontrolled eating. Depression mediated the association between PMDD and uncontrolled eating. The BMI of women with PMDD positively correlated with their EL-LL change in leptin, and LL depression levels and emotional eating. CONCLUSION: Young women with PMDD had higher leptin concentrations and BMI in the luteal phase. The LL leptin level was not the primary factor responsible for the increased uncontrolled eating of PMDD. Whether the increased eating and depression in the LL phase contribute to the risk of obesity or hyperleptinemia among women with PMDD need to be evaluated in the future.

Trait-related changes in brain network topology in premenstrual dysphoric disorder.

The female predominance in the prevalence of depression is partially accounted by reactivity to hormonal fluctuations. Premenstrual dysphoric disorder (PMDD) is a reproductive subtype of depression characterized by cyclic emotional and somatic symptoms that recur before menstruation. Despite the growing understanding that most psychiatric disorders arise from dysfunctions in distributed brain circuits, the brain's functional connectome and its network properties of segregation and integration were not investigated in PMDD. To this end, we examined the brain's functional network organization in PMDD using graph theoretical analysis. 24 drug naïve women with PMDD and 27 controls without premenstrual symptoms underwent 2 resting-state fMRI scans, during the mid-follicular and late-luteal menstrual cycle phases. Functional connectivity MRI, graph theory metrics, and levels of sex hormones were computed during each menstrual phase. Altered network topology was found in PMDD across symptomatic and remitted stages in major graph metrics (characteristic path length, clustering coefficient, transitivity, local and global efficiency, centrality), indicating decreased functional network segregation and increased functional network integration. In addition, PMDD patients exhibited hypoconnectivity of the anterior temporal lobe and hyperconnectivity of the basal ganglia and thalamus, across menstrual phases. Furthermore, the relationship between difficulties in emotion regulation and PMDD was mediated by specific patterns of functional connectivity, including connections of the striatum, thalamus, and prefrontal cortex. The shifts in the functional connectome and its topology in PMDD may suggest trait vulnerability markers of the disorder.

Early- and Late-Luteal-Phase Estrogen and Progesterone Levels of Women with Premenstrual Dysphoric Disorder.

: Objective/introduction: The dynamics of ovarian hormone fluctuations during the luteal phase of the menstruation cycle were previously suggested to contribute to the development of premenstrual dysphoric disorder (PMDD) symptoms, but adequate empirical evidence has not been obtained from hormone concentration studies. We prospectively evaluated estrogen and progesterone levels in the early luteal (EL) and late luteal (LL) phases in women with PMDD and the association of these levels with PMDD symptom severity. Methods: 63 women with PMDD and 53 controls without such severe symptoms were evaluated for the estrogen and progesterone levels, and PMDD severity in the EL and LL phases. Results: The results demonstrated that the women with PMDD had a lower EL-phase estrogen level than the controls. Covariant analysis demonstrated that the interaction term between EL-phase estrogen and EL-phase progesterone level was associated with PMDD severity. Among women with lower EL estrogen levels, higher EL-phase progesterone was observed among the women with PMDD versus controls. These results suggest that low EL-phase estrogen level could moderate the provoking effect of EL progesterone in women with PMDD. Overall, these data suggest a possible role of estrogen and progesterone in the development of PMDD symptoms.

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

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.

The Menstrual Cycle Influences Emotion but Has Limited Effect on Cognitive Function.

From a psychological perspective, the menstrual cycle has been a research topic for more than 50 years. The most recent menstrual cycle research has been driven by an increased interest in sex differences in neuroscience, and the urge to understand sex disparities in prevalence, clinical presentation, and treatment response in psychiatric or neurologic disorders. Indeed, the menstrual cycle is an excellent model of ovarian steroid influence on emotion, behavior, and cognition. This review summarizes the emotion-related and cognitive findings of methodologically sound menstrual cycle studies. In particular, the review is devoted to the sex hormone-induced emotional disturbances in women with premenstrual dysphoric disorder, a subgroup of women responding with enhanced sensitivity to the normal fluctuations in endogenous hormone levels during the menstrual cycle. In addition, emotion processing and cognitive findings across the menstrual cycle in healthy women are also discussed. The overall conclusion is that that menstrual cycle differences in sexually dimorphic cognitive tasks are small and difficult to replicate. Emotion-related changes are more consistently found and are better associated with progesterone and the luteal phase, than with estradiol.

Vitamin D Supplementation for Premenstrual Syndrome-Related Mood Disorders in Adolescents with Severe Hypovitaminosis D.

STUDY OBJECTIVE: Premenstrual syndrome (PMS) might become severe enough to interfere with normal interpersonal relationships. This study was planned to assess whether administration of vitamin D (200,000 IU at first, followed by 25,000 IU every 2 weeks) for a 4-month period might lessen the appearance and the intensity of mood disorders associated with PMS in young girls with severe hypovitaminosis D. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: One hundred fifty-eight young girls (15-21 years old) with PMS-related severe symptoms of the emotional and cognitive domains and low serum 25-hydroxycholecalciferol (25-OH-D) levels (≤10 ng/mL) were randomly assigned to two treatment groups and treated for 4 months with vitamin D (group 1; n = 80) or placebo (group 2; n = 78). Clinical and hormonal effects were compared between the two groups. RESULTS: In patients from group 1, levels of vitamin D reached the normal range (35-60 ng/mL) after the first month and remained stable throughout the whole study. At the end of treatment, anxiety score decreased from 51 to 20 (P < .001 vs baseline); irritability score declined from 130 to 70 (P < .001 vs baseline). Crying easily and sadness decreased by a score of 41 and 51 to a score of 30 and 31, respectively (P < .001). For disturbed relationships, the score decreased from 150 to 70 (P < .001). Conversely, no appreciable changes were noted in symptom intensity from patients of group 2. The frequency of adverse events (nausea and constipation) was not different between participants of group 1 and group 2. CONCLUSION: On the basis of the present findings, vitamin D therapy can be proposed as a safe, effective, and convenient method for improving the quality of life in young women with severe hypovitaminosis D and concomitant mood disorders associated with PMS.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder.

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

Beta-Arrestin1 Levels in Mononuclear Leukocytes Support Depression Scores for Women with Premenstrual Dysphoric Disorder.

Depression is very common in reproductive women particularly with premenstrual dysphoric disorder (PMDD), which is a severe form of premenstrual syndrome (PMS). Beta-arrestins were previously implicated in the pathophysiology, diagnosis and treatment for mood disorders. This study examined whether a measurement for beta-arrestin1 levels in peripheral blood mononuclear leukocytes (PBMC), could aid to distinguish between PMDD and PMS. Study participants (n = 25) were non-pregnant women between 18-42 years of age with the symptoms of PMS/PMDD, but not taking any antidepressants/therapy and at the luteal phase of menstruation. The levels of beta-arrestin1 protein in the PBMCs were determined by ELISA using human beta-arrestin1 kit. The beta-arrestin1 levels were compared with the Hamilton Depression Rating Scale scores among these women. The magnitude of the different parameters for Axis 1 mental disorders were significantly higher and beta arrestin1 protein levels in PBMCs were significantly lower in women with PMDD as compared to PMS women. The reduction in beta arrestin1 protein levels was significantly correlated with the severity of depressive symptoms. Beta-arrestin1 measurements in women may potentially serve for biochemical diagnostic purposes for PMDD and might be useful as evidence-based support for questionnaires.

Serum brain-derived neurotrophic factor differences between the luteal and follicular phases in premenstrual dysphoric disorder.

OBJECTIVE: We hypothesized that comparison of the serum brain-derived neurotrophic factor (BDNF) levels between women with premenstrual dysphoric disorder (PMDD) and women without PMDD in the luteal and follicular phases of their menstrual cycles would reflect the altered neuromodulator responses that compensate the underlying pathogenesis in PMDD. METHOD: Twenty-nine participants without PMDD and 20 with PMDD were enrolled in the study. The serum BDNF, estrogen and progesterone levels were assessed at the follicular and luteal phases in their two consecutive menstrual cycles. RESULTS: Participants with PMDD had significantly higher luteal serum BDNF levels than the control subjects. The serum BDNF levels were significantly higher in the luteal phase than in the follicular phase in women with PMDD. The difference in the serum BDNF levels between the luteal and follicular phases were significantly higher in the PMDD patients than in the control. CONCLUSIONS: The higher serum BDNF levels in the luteal phase in the PMDD patients may reflect compensatory process that results in subsequent improvement of the PMDD-associated depressive symptoms in the follicular phase. The higher difference in the serum BDNF levels between the phases in PMDD patients may reflect an altered neuromodulator response.

Gonadotrophic hormone and reinforcement sensitivity systems in women with premenstrual dysphoric disorder.

AIM: Behavior inhibition and behavior approach system (BIS/BAS) determine the sensitivity to aversion and rewarding stimuli, respectively. This study aimed at evaluating the BIS/BAS of premenstrual dysphoric disorder (PMDD) and effect of estrogen and progesterone on the BIS/BAS. METHODS: Women with PMDD without treatment and control subjects were recruited from the community. The PMDD diagnosis was based on psychiatric interviewing and the result of two-menstrual-cycle follow up. A total of 67 women with PMDD and 75 control subjects were recruited and entered the final analysis. They were evaluated with BIS/BAS scale and for estrogen and progesterone levels in both premenstrual and follicular phases. RESULTS: The results revealed that BAS score was higher among women with PMDD in both premenstrual and follicular phases. Progesterone level negatively correlated with fun-seeking, and its change in the menstrual cycle also negatively correlated to a change in fun-seeking score among women with PMDD. Women with PMDD had a higher score in BIS in the premenstrual phase and the BIS score correlated to depression, anxiety, and hostility among them. CONCLUSION: These results suggest reward sensitivity of women with PMDD is vulnerable to the effect of progesterone change in the menstrual cycle. Furthermore, the sensitivity to aversive stimuli plays an important role involving core symptoms of PMDD. The reinforcement sensitivity of PMDD deserves further detailed study.

The effect of serotonin 1A receptor polymorphism on the cognitive function of premenstrual dysphoric disorder.

Estrogen and serotonin play vital roles in the mechanism of premenstrual dysphoric disorder (PMDD). Cognitive deficit in the premenstrual phase contributes to impaired life function among women with PMDD. The aim of this study was to evaluate the difficulties in cognitive control and working memory (WM) in PMDD and to explore the effects of gonadotropic hormone and polymorphism of serotonin 1A receptor (HTR1A; rs6295) on cognitive deficit in PMDD. Women with PMDD completed diagnostic interviewing, questionnaire assessment, the Go/Nogo task, 2-back and 3-back tasks, and gonadotropic hormone analysis in the premenstrual and follicular phases. Further, they were followed up for two menstrual cycles to confirm two consecutive symptomatic cycles. A total of 59 subjects with PMDD and 74 controls completed all evaluation, fulfilled the criteria, and entered into the final analysis. The results demonstrated cognitive control and WM decline in the premenstrual among women with PMDD. The G/G genotype of HTR1A (rs6295) was found to be associated with impaired WM in the premenstrual phase and premenstrual decline of cognitive function. It also contributed to the vulnerability of cognitive function to the menstrual cycle effect and PMDD effect. As the G/G genotype of HTR1A (rs6295) involves in reducing serotonin neurotransmission, our results provide insight into the serotonin mechanism of cognitive function among women with PMDD.