Effectiveness and safety of Jiawei Xiaoyao pill in the treatment of premenstrual syndrome (liver depression, spleen deficiency, and blood-heat syndrome): a multi-center, randomized, placebo-controlled trial.

OBJECTIVE: To investigate the effectiveness and safety of Jiawei Xiaoyao pill (，JXP) in the treatment of symptoms associated with premenstrual syndrome (PMS). METHODS: A total of 144 regularly menstruating women with PMS were recruited at 8 sites in China from August 2017 to December 2018, and randomized to receive either a JXP or a matching placebo (12 g/d, 6 g twice a day) for 3 menstrual cycles. The primary indicator was the reduced Daily Record of Severity of Problems (DRSP) scores in the luteal phase after 3 months of treatment. The safety outcomes included clinical adverse events (AEs), adverse reactions (ARs), changes in vital signs, and laboratory tests. RESULTS: JXP surpassed the placebo in reducing DRSP scores (psychological/somatic dysfunction) in the luteal phase over 3 menstrual cycles of treatment (PFAS = 0.002, PPPS = 0.001). Additionally, there were no significant differences in the incidence of AEs, severe AEs, withdrawal due to AEs and ARs between the two groups (all P > 0.05), and no clinically significant adverse medical events related to the test drug observed. CONCLUSIONS: JXP was superior to the placebo in relieving the symptoms associated with PMS, which signified that JXP may be effective, safe, and well-tolerated as an alternative therapy.

[Premenstrual syndrome and premenstrual dysphoric disorder-Overview on pathophysiology, diagnostics and treatment]. / Prämenstruelles Syndrom und prämenstruelle dysphorische Störung ­ Übersicht zu Pathophysiologie, Diagnostik und Therapie.

Premenstrual syndrome and premenstrual dysphoric disorder become episodically manifest during the second half of the female menstrual cycle and are characterized by psychological and physical symptoms causing relevant functional and social impairments. Mood swings, depression and dysphoria are associated depressive symptoms. Therefore, affective disorders should be considered as a differential diagnosis. Of women in reproductive age 3-8% suffer from premenstrual syndrome and 2% of women are affected by premenstrual dysphoric disorder. Genetic and sociobiographical risk factors are discussed. Furthermore, genetic polymorphisms of specific hormone receptors are considered to be genetic risk factors. From a pathophysiological perspective premenstrual syndrome and premenstrual dysphoric disorder are caused by a complex interaction between cyclic changes of ovarian steroids and central neurotransmitters. An imbalance of estrogen and progesterone in the luteal phase is believed to cause the symptoms. Therefore, the first treatment approach consists of regulation of the menstrual cycle or luteal support with progesterone or synthetic progestins even if their effectiveness has not yet been proven in randomized controlled studies and meta-analyses. The administration of combined oral contraceptives is also an option. Especially treatment with selective serotonin reuptake inhibitors (SSRI) represent an evidence-based approach. In severe cases the administration of gonadotropin releasing hormone (GnRH) agonists with add back treatment can also be considered. In the field of affective disorders premenstrual syndromes represent clinically relevant differential diagnoses and comorbidities, which confront the treating physician with particular clinical challenges. Therefore, this literature review gives the readership a clinical orientation for dealing with these disorders.

Effect of vitamin D supplementation on symptoms severity in vitamin D insufficient women with premenstrual syndrome: A randomized controlled trial.

BACKGROUND: Premenstrual syndrome (PMS) is one of the most prevalent disorders among reproductive women worldwide that negatively impact women's quality of life. This study aimed to investigate the effect of vitamin D supplementation on the severity of PMS symptoms in vitamin D insufficient women with PMS. METHODS: In this randomized, double-blind clinical trial, 44 vitamin D insufficient women with PMS received either 50,000 IU vitamin D or a placebo fortnightly for 16 weeks. Participants completed the PMS Daily Symptoms Rating form at beginning and during the last two months of the intervention, and their blood samples were collected to assess 25(OH)D serum levels. RESULTS: After the four months' intervention, the serum level of 25(OH)D in the vitamin D group raised from 21 ± 8 ng/ml to 40 ± 8 ng/ml (P < 0.001), while in the placebo group it raised from 21 ± 7 ng/ml to 23 ± 7 ng/ml (P = 0.03). Indeed, serum vitamin D levels in the placebo group could not reach a sufficient level. At the end of the intervention, the mean score of total PMS symptoms showed significant improvement in the vitamin supplemented group compared to the controls (p < 0.001). By grouping the PMS symptoms into five subgroups, the mean score of all five subgroups decreased post-supplementation compared to the baseline; however, the highest and lowest decrease were in depression (53 %) and water retention subgroups (28 %), respectively. This indicates a greater improvement in the mean scores of mood symptoms compared to physical symptoms in this study (p < 0.001). CONCLUSION: Results obtained in this clinical trial represent the helpful effects of vitamin D supplementation on total, physical and mood symptoms in vitamin D insufficient women with PMS. TRIAL REGISTRATION: This randomized controlled trial at IRCT.ir on 2018-06-20 with Registration No: IRCT20180525039822N1.

GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder.

RATIONALE: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. AIMS: The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. METHODS: Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5ß-THP; pregnenolone; 3α,5α-androsterone; 3α,5ß-androsterone; 3α,5α-A-diol; 3α5ß-A-diol; 3α,5α-THDOC; 3α5ß-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. RESULTS: Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. CONCLUSIONS: This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.

Vitex agnus castus effects on hyperprolactinaemia.

Background: Vitex agnus castus (VAC), also known as chaste tree, is a plant from the Mediterranean area, Crimea, and central Asia. Its fruit has been used for more than 2500 years as phytotherapic agent. In the last century, VAC has been mostly used for the treatment of premenstrual syndrome (PMS), menstrual irregularities, fertility disorders, and symptoms of menopause. Since some degree of hyperprolactinaemia may be observed in patients with such disorders, VAC effects on hyperprolactinaemia have been assessed in a small number of studies and in some patient series or single case reports. It has been postulated that the diterpenes contained in VAC extract may interact with dopamine D2 receptors (D2R) and inhibit prolactin release via dopamine D2R activation in the anterior pituitary. Most of the published papers focus on the use of VAC for the management of PMS or infertility. However, due to its action on D2R, VAC could have a role in the treatment of mild hyperprolactinaemia, including patients with idiopathic hyperprolactinaemia, microprolactinoma, drug-induced hyperprolactinaemia, or polycystic ovary syndrome. Methods: We have reviewed and analysed the data from the literature concerning the use of VAC extracts in patients with hyperprolactinaemia. Results: Some evidence suggests a possible role of VAC for the management of hyperprolactinaemia in selected patients, though in an inhomogeneous way. However, there are not any large randomized controlled trials supporting the same and the precise pharmacological aspects of VAC extract in such a clinical setting still remain obscure. Conclusion: It appears that VAC may represent a potentially useful and safe phytotherapic option for the management of selected patients with mild hyperprolactinaemia who wish to be treated with phytotherapy. However, larger studies of high quality are needed to corroborate it.

Lactobacillus paragasseri OLL2809 Improves Premenstrual Psychological Symptoms in Healthy Women: A Randomized, Double-Blind, Placebo-Controlled Study.

Lactobacillus paragasseri OLL2809 has been shown to ameliorate stress. This study employed a randomized, placebo-controlled, double-blind, parallel-group design to assess the efficacy of continuous ingestion of OLL2809 for managing menstrual symptoms in healthy women. Eighty healthy adult women aged 25-40 years who experienced premenstrual and menstrual symptoms were randomly assigned to either the OLL2809 or placebo group (n = 40 each) and ingested tablets containing OLL2809 or placebo for three menstrual cycles. The OLL2809 group exhibited a significantly greater change in premenstrual 'arousal' scores on the menstrual distress questionnaire compared to the placebo group after the three menstrual cycles. Specifically, changes in the 'activity' subfactor were significantly higher in the OLL2809 group than in the placebo group. Additionally, the OLL2809 group reported significantly lower premenstrual irritability on the visual analog scale than the placebo group. These results suggest that OLL2809 may contribute to enhancing the quality of life of women.

The multifactorial aetiology and management of premenstrual dysphoric disorder with leuprorelin acetate.

Up to 18% of women of reproductive age may experience symptoms during the luteal phase of the menstrual cycle known as premenstrual syndrome (PMS) or its more severe form, premenstrual dysphoric disorder (PMDD). A plethora of symptoms have been described, but both are commonly associated with other mood-related disorders such as major depression causing significant life impairment. Originally known as late luteal phase dysphoric disorder in the DSM-III-R (American Psychiatric Association 1987), the syndrome was renamed PMDD in the DSM-IV (American Psychiatric Association 1994). Between 3% and 8% of women meet the diagnostic criteria for PMDD. Currently, there is no consensus on its aetiology although it is thought to be multifactorial. Biological, genetic, psychological, environmental and social factors have all been suggested. However, an altered sensitivity to the normal hormonal fluctuations that influence functioning of the central nervous system is thought most likely. PMDD is identified in the DSM-5 by the presence of at least five symptoms accompanied by significant psychosocial or functional impairment. During evaluation, it is recommended that clinicians confirm symptoms by prospective patient mood charting for at least two menstrual cycles. Management options include psychotropic agents, ovulation suppression and dietary modification. Selective serotonin reuptake inhibitors (SSRIs) are considered primary therapy for psychological symptoms. Ovulation suppression is another option with the combined oral contraceptive pill (COCP) or GnRH (gonadotropin-releasing hormone) agonists. Rarely symptoms warrant a bilateral oophorectomy and a 6-month trial of GnRH agonists prior to surgery may be prudent to determine its potential efficacy. The authors present the case of a multiparous woman in her mid-30s experiencing severe symptoms during the luteal phase of her menstrual cycle. A trial of the contraceptive pill and SSRIs were unsuccessful. Treatment with leuprorelin acetate (Prostap) improved her symptoms. She therefore elected to undergo a bilateral oophorectomy with resolution of her symptoms. She started hormone replacement therapy (HRT). This case demonstrates the multifactorial aetiology of PMDD and the challenges in its management. Women with PMDD suffer functional impairments comparable with other depressive disorders and yet PMDD and its impact remain under-recognised. As the psychological nature and consequences of PMDD often seem indistinguishable from symptoms of other mental health difficulties, this condition presents distinct diagnostic challenges for healthcare professionals. It is crucial to establish the correct diagnosis using clearly defined criteria because if it is left untreated, it can cause considerable impairment to the woman's quality of life.

A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE. SCOPING REVIEW STRUCTURED SUMMARY: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms. OBJECTIVE: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable. CHARTING METHODS: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial. RESULTS: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders. CONCLUSIONS: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Low doses of fluoxetine for the treatment of emotional premenstrual syndrome: a randomized double-blind, placebo-controlled, pilot study.

INTRODUCTION: The neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested that low doses of fluoxetine increase the ALLO brain concentration. OBJECTIVES: To assess which low dose of fluoxetine (2 mg/d, 5 mg/d or 10 mg/d), administered exclusively during the luteal phase of menstrual cycle, has a potential effect for preventing or mitigating emotional PMS symptoms. METHODS: In this randomized, double-blind, placebo-controlled pilot study, we followed 40 women (mean age = 29.7 +/- 7.4 years) with emotional PMS, during two menstrual cycles: cycle 1, without pharmacological intervention; and cycle 2, with pharmacological intervention. Participants took capsules, on average, seven days preceding the likely date of menses. We assessed the severity of PMS symptoms in both cycles using the Daily Record of Severity of Problems scale (DRSP). RESULTS: There was an increase in the DRSP scores during the late luteal phase of cycle 1, confirming the diagnosis of emotional PMS. Low doses of fluoxetine (5 mg/d: 33.5%; 10 mg/d: 48.4%) reduced DRSP total score in the day before menses (day-1) at cycle 2 compared with day-1 at cycle 1. Fluoxetine 10 mg/d had the most consistent decline in emotional PMS symptoms; 70% of the participants reported a reduction greater than 40% in the DRSP score. CONCLUSIONS: Low doses of fluoxetine, which may have no or few effect on the serotonergic system, but may interfere in the progesterone metabolization, seem to have some potential to mitigate emotional PMS symptoms. While the 10 mg/d of fluoxetine had the best performance on reducing emotional PMS symptoms, the 5 mg/d dose also seems to have some effect on emotional PMS symptoms. Further larger studies will help establish the lowest effective dose of flouxetine for PMS treatment.

GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder.

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.

Phyto-progestins for the treatment of abnormal uterine bleeding without organic cause in women at high risk for breast cancer and breast cancer survivors: a prospective, pilot study.

OBJECTIVES: Some plants, such as Dioscorea Villosa (DV), Vitex Agnus Castus (VAC) and Turnera diffusa (D) have some 'progesterone-like' properties. We have investigated their simultaneous administration in breast cancer (BC) survivors or carriers of specific genetic mutations that can increase the risk of developing BC suffering from abnormal uterine bleeding without organic cause. METHODS: Women with irregular cycles in terms of length (interval between ≤ 24 or ≥ 38 days) without a uterine organic disease (polyps, adenomyosis, fibroids, hyperplasia/malignancy) were included. A daily diary of bleeding, questionnaires about health-related quality of life (Short Form 36) and menstrual psychophysical well-being (PGWB-1) and the Greene Climacteric Scale (GCS) (in women older than 40 years old) questionnaire were used. The presence of some premenstrual syndrome (PMS) symptoms was also evaluated. RESULTS: In the analyzed group of women (n = 15), all experienced a regularization of the menstrual cycles, with a mean duration in the three months of use of 27.1 ± 3.2 days, with a significant reduction of menstrual pain (p = 0.02) and flow (p = 0.02) intensity. Women with PMS (7/15) reported an impovement in depression, headache and abdominal pain scores (p < 0.05). No specific deterioration of different questionnaires evaluated during treatment were observed. General satisfaction with the treatment was 6.8 ± 0.3/10 on a 10 point. CONCLUSIONS: A combination of DV, VAC and D could be a promising candidate to treat menstrual irregularities without an organic cause, with a significant reduction of menstrual pain and flow intensity and possible additional benefits in PMS symptoms treatment in women at genetic risk for BC and BC survivors.

Limbic self-neuromodulation as a novel treatment option for emotional dysregulation in premenstrual dysphoric disorder (PMDD); a proof-of-concept study.

AIM: To assess the efficacy of a novel neurofeedback (NF) method, targeting limbic activity, to treat emotional dysregulation related to premenstrual dysphoric disorder (PMDD). METHODS: We applied a NF probe targeting limbic activity using a functional magnetic resonance imaging-inspired electroencephalogram model (termed Amyg-EFP-NF) in a double-blind randomized controlled trial. A frontal alpha asymmetry probe (AAS-NF), served as active control. Twenty-seven participants diagnosed with PMDD (mean age = 33.57 years, SD = 5.67) were randomly assigned to Amyg-EFP-NF or AAS-NF interventions with a 2:1 ratio, respectively. The treatment protocol consisted of 11 NF sessions through three menstrual cycles, and a follow-up assessment 3 months thereafter. The primary outcome measure was improvement in the Revised Observer Version of the Premenstrual Tension Syndrome Rating Scale (PMTS-OR). RESULTS: A significant group by time effect was observed for the core symptom subscale of the PMTS-OR, with significant improvement observed at follow-up for the Amyg-EFP group compared with the AAS group [F(1, 15)=4.968, P = 0.042]. This finding was specifically robust for reduction in anger [F(1, 15) = 22.254, P < 0.001]. A significant correlation was found between learning scores and overall improvement in core symptoms (r = 0.514, P = 0.042) suggesting an association between mechanism of change and clinical improvement. CONCLUSION: Our preliminary findings suggest that Amyg-EFP-NF may serve as an affordable and accessible non-invasive treatment option for emotional dysregulation in women suffering from PMDD. Our main limitations were the relatively small number of participants and the lack of a sham-NF placebo arm.

What's Stopping Us? Using GnRH Analogs With Stable Hormone Addback in Treatment-Resistant Premenstrual Dysphoric Disorder: Practical Guidelines and Risk-Benefit Analysis for Long-term Therapy.

Objective: Despite the documented success of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of treatment-resistant premenstrual dysphoric disorder (PMDD), many patients struggle to find providers who have sufficient knowledge of PMDD and its evidence-based treatments and/or who are comfortable treating PMDD after first-line treatment options have failed. Here, we discuss the barriers to initiating GnRHa for treatment-resistant premenstrual dysphoric disorder (PMDD) and offer practical solutions to address these barriers for providers who encounter patients with treatment-resistant PMDD but may not have the necessary expertise or comfort with providing evidence-based treatments (ie, gynecologists, general psychiatrists). We have included supplementary materials including patient and provider handouts, screening tools, and treatment algorithms with the hope that this review may serve as a primer on PMDD and the use of GnRHa with hormonal addback as a treatment, as well as a guideline for clinicians delivering this treatment to patients in need.Options: In addition to offering practical treatment guidelines for first and second lines of treatment for PMDD, this review offers an in-depth discussion of GnRHa for treatment-resistant PMDD.Outcomes: The burden of illness in PMDD is estimated to be similar to that of other mood disorders, and those suffering from PMDD are at a high risk for suicide.Evidence: We present a selective review of relevant clinical trials evidence supporting the use of GnRHa with addback hormones in treatment-resistant PMDD (the most recent evidence cited was published in 2021), highlighting the rationale for addback hormones and presenting the different possible hormonal addback approaches.Values: The PMDD community has and continues to suffer from debilitating symptoms despite the known interventions. This article provides guidance for implementing GnRHa into practice among a broader scope of clinicians including general psychiatrists.Benefits, Harms, and Costs: The primary benefit of implementing this guideline is that a broad range of clinicians beyond reproductive psychiatrists who encounter patients with PMDD will have a template for assessing and treating PMDD and implementing GnRHa treatment when first-line treatments fail. Harms are expected to be minimal; however, some patients may have side effects or adverse reactions to the treatment or may not respond as they had hoped. Costs of GnRHa can be high depending on insurance coverage. We provide information within the guideline to help navigate this barrier.Recommendations: (1) Prospective symptom rating in evaluating for PMDD is necessary for diagnosis and evaluating treatment response. (2) SSRIs and oral contraceptives should be trialed as the first- and second-line treatments for PMDD. (3) When first- and second-line treatments have failed to yield symptom relief, the use of GnRHa with hormone addback should be considered. Risks and benefits of GnRHa should be weighed among clinicians and patients, and potential barriers to access should be discussed.Validation: This article adds to the available systematic reviews on the effectiveness of GnRHa in the treatment of PMDD and Royal College of Obstetrics and Gynecology's guidelines on the treatment of PMDD.

Oral contraceptives containing drospirenone for premenstrual syndrome.

BACKGROUND: Premenstrual syndrome (PMS) is a common problem. Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome. Combined oral contraceptives (COC), which provide both progestin and oestrogen, have been examined for their ability to relieve premenstrual symptoms. A combined oral contraceptive containing drospirenone and a low oestrogen dose has been approved for treating PMDD in women who choose combined oral contraceptives for contraception. OBJECTIVES: To evaluate the effectiveness and safety of COCs containing drospirenone in women with PMS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group trial register, CENTRAL (now containing output from two trials registers and CINAHL), MEDLINE, Embase, PsycINFO, LILACS, Google Scholar, and Epistemonikos on 29 June 2022. We checked included studies' reference lists and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCT) that compared COCs containing drospirenone with placebo or with another COC for treatment of women with PMS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were effects on premenstrual symptoms that were prospectively recorded, and withdrawal due to adverse events. Secondary outcomes included effects on mood, adverse events, and response rate to study medications. MAIN RESULTS: We included five RCTs (858 women analysed, most diagnosed with PMDD). The evidence was very low to moderate quality; the main limitations were serious risk of bias due to poor reporting of study methods, and serious inconsistency and imprecision. COCs containing drospirenone and ethinylestradiol (EE) versus placebo COCs containing drospirenone and EE may improve overall premenstrual symptoms (standardised mean difference (SMD) -0.41, 95% confidence interval (CI) -0.59 to -0.24; 2 RCTs, N = 514; I2 = 64%; low-quality evidence); and functional impairment due to premenstrual symptoms in terms of productivity (mean difference (MD) -0.31, 95% CI -0.55 to -0.08; 2 RCTs, N = 432; I2 = 47%; low-quality evidence), social activities (MD -0.29, 95% CI -0.54 to -0.04; 2 RCTs, N = 432; I2 = 53%; low-quality evidence), and relationships (MD -0.30, 95% CI -0.54 to -0.06; 2 RCTs, N = 432; I2 = 45%; low-quality evidence). The effects from COCs containing drospirenone may be small to moderate. COCs containing drospirenone and EE may increase withdrawal from trials due to adverse effects (odds ratio (OR) 3.41, 95% CI 2.01 to 5.78; 4 RCT, N = 776; I2 = 0%; low-quality evidence). This suggests that if you assume the risk of withdrawal due to adverse effects from placebo is 3%, the risk from drospirenone plus EE will be between 6% and 16%. We are uncertain of the effect of drospirenone plus EE on premenstrual mood symptoms, when measured by validated tools that were not developed to assess premenstrual symptoms. COCs containing drospirenone may lead to more adverse effects in total (OR 2.31, 95% CI 1.71 to 3.11; 3 RCT, N = 739; I2 = 0%; low-quality evidence). This suggests that if you assume the risk of having adverse effects from placebo is 28%, the risk from drospirenone plus EE will be between 40% and 54%. It probably leads to more breast pain, and may lead to more nausea, intermenstrual bleeding, and menstrual disorder. Its effect on nervousness, headache, asthenia, and pain is uncertain. There was no report of any rare but serious adverse effects, such as venous thromboembolism in any of the included studies. COCs containing drospirenone may improve response rate (OR 1.65, 95% CI 1.13 to 2.40; 1 RCT, N = 449; I2 not applicable; low-quality evidence). This suggests that if you assume the response rate from placebo is 36%, the risk from drospirenone plus EE will be between 39% and 58%. We did not identify any studies that compared COCs containing drospirenone with other COCs. AUTHORS' CONCLUSIONS: COCs containing drospirenone and EE may improve premenstrual symptoms that result in functional impairments in women with PMDD. The placebo also had a significant effect. COCs containing drospirenone and EE may lead to more adverse effects compared to placebo. We do not know whether it works after three cycles, helps women with less severe symptoms, or is better than other combined oral contraceptives that contain a different progestogen.

New Pharmacological Approaches to the Management of Premenstrual Dysphoric Disorder.

Premenstrual symptoms are experienced by many female individuals during their fertile age. Premenstrual dysphoric disorder (PMDD), a sex-specific mood disorder, affects about 5% of female individuals during the luteal phase of the menstrual cycle. Treatment with selective serotonin reuptake inhibitors represents a valid solution to manage PMDD for many, but not all, patients. Owing to maladaptive neural reactivity to gonadal hormone fluctuations, that is, the putative mechanism postulated to underlie PMDD, drugs suppressing or stabilizing such variations have been tested. Recently, a clinically significant reduction in the severity of the mental symptoms of PMDD was observed upon treatment with a selective progesterone receptor modulator (SPRM), as demonstrated when comparing ulipristal acetate with placebo in a randomised controlled trial. Stable and low progesterone levels, with maintained low-medium oestradiol levels, define the endocrine profile of this treatment. Importantly, the efficacy of SPRM treatment was accompanied by negligible side effects. These promising results represent a headway to understanding the mechanisms behind PMDD symptomatology and opening up new solutions in the management of PMDD. They also call for studies on the long-term efficacy, safety, and viability of SPRMs in female individuals during their fertile age to further support the development of targeted management of female's mental ill-health in relation to the menstrual cycle. The present overview thus seeks to inform about current and new pharmacological approaches to the management of premenstrual dysphoric disorder.

Does Symptom-Onset Treatment With Sertraline Improve Functional Impairment for Individuals With Premenstrual Dysphoric Disorder?: A Randomized Controlled Trial.

PURPOSE/BACKGROUND: Daily treatment with sertraline improves functional impairment among individuals with premenstrual dysphoric disorder (PMDD). We do not know whether treatment initiated at symptom onset also improves functional impairment. METHODS/PROCEDURES: This 3-site, double blind, randomized, clinical trial compared sertraline (25-100 mg) to similar appearing placebo, both administered at symptom onset, for reduction of PMDD symptoms. Ninety participants were allocated to sertraline and 94 participants to placebo. Functional outcomes from the Daily Ratings of the Severity of Problems included (1) reduced productivity or efficiency at work, school, home, or daily routine; (2) interference with hobbies or social activities; and (3) interference with relationships. Items were measured from 1 (no interference) to 6 (extreme interference) and averaged for the final 5 luteal phase days. This secondary analysis examined whether improvement in functional domains was greater for those allocated to sertraline compared with placebo. Second, we used causal mediation analyses to explore whether specific PMDD symptoms mediated functional improvement. RESULTS/FINDINGS: Only relationship functioning improved significantly with active treatment between baseline and the end of the second cycle (active group mean [SD] change, -1.39 [1.38]; placebo group mean change, -0.76 [1.20]; ß = -0.40; SE, 0.15; P = 0.009). The total effect of treatment on interference was -0.37 (95% confidence interval [CI], -0.66 to -0.09; P = 0.011). Given the nonsignificant direct effect (0.11; 95% CI, -0.07 to 0.29; P = 0.24) and significant indirect effect (-0.48; 95% CI, -0.71 to -0.24; P < 0.001), amelioration of anger/irritability likely mediated reductions in relationship interference. IMPLICATIONS/CONCLUSIONS: That anger/irritability mediates impairments in relationship functioning has face validity but should be replicated in other data sets. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00536198 .

Effect of γ-tocopherol supplementation on premenstrual symptoms and natriuresis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: This randomized, double-blind, placebo-controlled study aimed to investigate the effects of γ-tocopherol (Toc) supplementation on premenstrual symptoms and natriuresis. METHODS: We enrolled 51 Japanese women with premenstrual symptoms, particularly those who showed increased symptoms induced by water retention during the luteal phase compared with the follicular phase. Premenstrual symptoms were recorded in the first cycle's postmenstrual follicular phase; physical measurements and urine collection were conducted during the 48-h run-in period. The test supplement, which contained 180 mg of γ-Toc or placebo, was orally administered twice a day for 7 days during the luteal phase of the first and second cycles in a crossover manner. The same evaluation was conducted during the luteal phase, beginning in the morning of the sixth day of supplement administration. RESULTS: Compared with placebo intake, γ-Toc intake significantly reduced "fatigue" and "irritability/anger" symptoms. Furthermore, compared with placebo intake, γ-Toc intake significantly reduced the thigh circumference. Regarding the "swelling of the legs" and "heavy legs" symptoms and the thigh circumference, the biphasic trend of increasing and decreasing values in the daytime and morning, respectively, during the follicular phase was not observed at the luteal phase with placebo intake. Contrastingly, γ-Toc intake resulted in significantly lower values in the morning than placebo intake. The mean difference in 24-h urinary sodium excretion between γ-Toc and placebo intake was 10.6 mEq (95% confidence interval (CI): -0.1, 21.4, p = 0.05, power 55%). Plasma γ-Toc and its metabolite γ-carboxyethyl hydroxychroman (CEHC) levels were significantly higher with γ-Toc intake than with placebo intake. There were no significant between-supplement differences in serum electrolyte levels or cumulative urinary potassium excretion. CONCLUSION: γ-Toc intake could effectively alleviate certain premenstrual syndrome symptoms, particularly those related to water retention during the luteal phase. Furthermore, the underlying mechanism may involve the diuretic effect of γ-CEHC, which is a γ-Toc metabolite. TRIAL REGISTRATION: UMIN000047989; registration date: 10/06/2022, retrospectively registered.

Efficacy of Curcumin on Cognitive Function Scores in Women with Premenstrual Syndrome and Dysmenorrhea: A Triple-Blind, Placebo-Controlled Clinical Trial.

OBJECTIVE: To assess the efficacy of a curcumin supplementation on cognitive abilities in women suffering from premenstrual syndrome (PMS) and dysmenorrhea. METHODS: A randomized, triple-blind, placebo-controlled trial was conducted from December 2019 to March 2020. A total of 124 women who had both PMS and dysmenorrhea were enrolled, and were equally and randomly assigned to the curcumin group or placebo group, 62 cases in each. Each subject received either a capsule containing 500 mg of curcuminoid, or a placebo daily, for 10 days (7 days before and until 3 days after the onset of menstrual bleeding) over 3 menstrual cycles. The cognitive abilities questionnaire was used to measures cognitive functions in 7 specific areas. Adverse reactions were monitored during and after the trial in both groups. RESULTS: Administration of curcumin was associated with a significant increase in memory score (P=0.002), inhibitory control and selective attention (P=0.020), and total cognitive ability task (P=0.024). In addition, significant increments were found in scores of memory (3.5±3.1 vs. 0.4±3.8 in the curcumin and placebo groups, respectively; P=0.035), inhibitory control and selective attention (3.0±3.7 vs. 0.4±3.7; P=0.027) and total cognitive abilities (8.3±12.3 vs. 2.2±12.4; P=0.025) in the curcumin group versus placebo groups. Curcumin was safe and well-tolerable in current clinical trial. CONCLUSION: Curcumin has a beneficial efficacy on cognitive function scores in women with PMS and dysmenorrhea, with improvements in memory, inhibitory control and selective attention. (Registration No. IRCT20191112045424N1, available at: https://www.irct.ir ).

El alivio natural: Sauzgatillo (Vitex agnus-castus) para el síndrome premenstrual y la dismenorrea / The natural relief: Chasteberry (Vitex agnus-castus) for premenstrual syndrome and dysmenorrhea

El síndrome premenstrual es un trastorno común en mujeres en edad reproductiva y se caracteriza por al menos un síntoma físico, emocional o conductual, que aparece en la fase lútea del ciclo menstrual y se resuelve poco después del inicio de la menstruación. Los tratamientos convencionales para el dolor perimenstrual cíclico tienen inconvenientes que incluyen efectos secundarios, interferencia con la función reproductiva de las mujeres o escasa efectividad en el alivio de los síntomas. Muchas mujeres recurren a terapias naturales para tratar una gran variedad de síntomas menstruales. Esta revisión se centra en una de esas opciones naturales, el Sauzgatillo (Vitex agnus-castus). Se realizó una búsqueda e identificación de artículos publicados hasta mayo de 2022 recopilados por medio de sistemas de búsqueda electrónicos como Google Scholar, Medline, PubMed y Scopus. Las palabras de búsqueda fueron: “Premenstrual syndrome”, “dysmenorrhea” AND “Vitex agnus-castus”. Los estudios preclínicos señalan un mecanismo de acción en su implicación sobre el sistema serotoninérgico, así como su unión a los receptores de dopamina. Los estudios clínicos demuestran la seguridad y el efecto positivo sobre el síndrome premenstrual y la dismenorrea.

Premenstrual syndrome is a common disorder in women of reproductive age and is characterized by at least one physical, emotional, or behavioral symptom, which appears in the luteal phase of the menstrual cycle and resolves shortly after the onset of menstruation. Conventional treatments for cyclical perimenstrual pain have drawbacks that include side effects, interference with womens reproductive function, or limited effectiveness in relieving symptoms. Many women turn to natural therapies to treat a wide variety of menstrual symptoms. This review focuses on one of those natural options, Chasteberry (Vitex agnus-castus). The information available until May 2022 was collected via the library and electronic search systems such as Google Scholar, Medline, PubMed, and Scopus. The search words were: “Premenstrual syndrome”, “dysmenorrhea” AND “Vitex agnus-castus”. Preclinical studies point to a mechanism of action in its involvement in the serotoninergic system, as well as its binding to dopamine receptors. Clinical studies prove safety and positive effect on premenstrual syndrome and dysmenorrhea.

New insights on the impact of gut microbiota on premenstrual disorders. Will probiotics solve this mystery?

Premenstrual disorders (PMDs) refer to premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), where both are characterized by physical and psychological changes occurring in the luteal phase of menstrual cycle. According to the available theories, there is no single accusation succeeded to explain the pathophysiology of PMDs. However, there is emerging evidence for the role of gut microbiota (GM) in PMDs, supported by the diverging impact of GM on our body systems. The direct secretory function of GM and their integration in hormonal, neurotransmitters and bioactive compounds secretion and activity reinforce this speculation. Moreover, the bidirectional relation between GM and steroid hormones and the impact of diet, drugs, and inflammation on both, GM and PMDs incidence and severity justify the need for more studies to determine the actual role of GM in PMDs and the possible potential of probiotics and prebiotics as therapeutic options.