Ge-gen decoction alleviates primary dysmenorrhoea symptoms in a rat model.

BACKGROUND: Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. Ge-Gen decoction (GGD), a traditional Chinese medicine, has shown promise in treating PD, but its exact mechanisms remain unclear. Here, we aimed to investigate the efficiency of GGD in alleviating PD using a rat model to understand its precise mechanism of action. METHODS: We established a rat model of dysmenorrhoea induced by oestradiol and oxytocin. The PD rats were administered GGD or Ibuprofen (positive control) intragastrically once daily for seven consecutive days. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), ß-endorphin (ß-EP), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression levels of oestrogen receptor alpha (ERα) and cyclooxygenase-2 (COX-2) in uterine tissue were measured using immunohistochemical assays, and those of phosphorylated and total extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were assessed using western blot analysis. RESULTS: Treatment with GGD significantly reduced writhing behaviour, histopathological scores, and levels of COX-2, PGE2, and PGF2α in the serum of PD rats. Additionally, GGD increased ß-EP content and inhibited ERK1/2 activation and ERα expression in uterine tissues. CONCLUSIONS: The results of this study suggest that GGD alleviates PD in rats by suppressing the COX-2-mediated release of PGE2 and PGF2α, modulating the ERα/ERK1/2/COX-2 pathway, and increasing ß-EP content. These results provide insights into the potential mechanisms of GGD in treating PD and support its further investigation as an alternative therapy for this condition.

Ge-Gen decoction is commonly used to alleviate primary dysmenorrhoea. However, its anti-dysmenorrhoea mechanism remains elusive. In this study, using a rat model of primary dysmenorrhoea, we demonstrate that Ge-Gen decoction reduced the levels of cyclooxygenase-2, prostaglandin E2, and prostaglandin F2 alpha in serum and phosphorylated extracellular signal-regulated protein kinases 1 and 2 in the uterus. These results suggest that Ge-Gen decoction alleviates primary dysmenorrhoea via inactivation of the oestrogen receptor alpha/extracellular signal-regulated protein kinases 1 and 2/cyclooxygenase-2 pathway. This study enhances our understanding of the pathogenesis of primary dysmenorrhoea and may potentially inform the development of novel treatment approaches.

Vitamin D Supplementation for Patients with Dysmenorrhoea: A Meta-Analysis with Trial Sequential Analysis of Randomised Controlled Trials.

Vitamin D reduces prostaglandin levels and inflammation, making it a promising treatment option for dysmenorrhoea. However, its effects on pain intensity in different types of dysmenorrhoea remain unclear. We examined whether vitamin D supplementation decreases pain intensity in patients with dysmenorrhoea. The Cochrane Library, Embase, Google Scholar, Medline, and Scopus databases were searched from inception to 30 December 2023. Randomised controlled trials (RCTs) evaluating vitamin D supplementation effects on such patients were included. The primary and secondary outcomes were measured by the changes in pain intensity and rescue analgesic use, respectively. Pooled mean differences and rate ratios were calculated using a random-effect model; trial sequential analysis (TSA) was also performed. Overall, 11 studies involving 687 participants were included. Vitamin D supplementation significantly decreased pain intensity in patients with dysmenorrhoea compared with controls (pooled mean difference, -1.64; 95% confidence interval, -2.27 to -1.00; p < 0.001; CoE, moderate; I2 statistic, 79.43%) and indicated substantial heterogeneity among the included studies. TSA revealed that the current RCTs provide sufficient information. In subgroup analyses, vitamin D supplement reduced primary dysmenorrhoea pain but not secondary dysmenorrhoea pain. In conclusion, although substantial heterogeneity persists, vitamin D supplementation decreased pain intensity in patients with dysmenorrhea, especially in those with primary dysmenorrhoea.

Investigational drugs for the treatment of dysmenorrhea.

INTRODUCTION: Dysmenorrhea is the most common cause of gynecological pain among women that has considerable impact on quality of life and psychosocial wellbeing. Non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies are most commonly used to treat dysmenorrhea. However, given these drugs are often associated with bothersome side effects and are less effective when there is an underlying cause contributing to dysmenorrhea (e.g. endometriosis), a patient-centered approach to managing dysmenorrhea is important. Various new drugs are currently being investigated for the treatment of primary and secondary dysmenorrhea. AREAS COVERED: This review provides an updated overview on new therapeutic targets and investigational drugs for the treatment of primary and secondary dysmenorrhea. The authors describe the clinical development and implications of these drugs. EXPERT OPINION: Among the investigative drugs discussed in this review, anti-inflammatories show the most promising results for the treatment of dysmenorrhea. However, given some trials have considerable methodological limitations, many drugs cannot be currently recommended. Research focused on understanding the mechanisms involved in menstruation and its associated symptoms will be important to identify new therapeutic targets for dysmenorrhea. Further robust clinical trials are required to better understand the efficacy and safety of investigational drugs for treating primary and secondary dysmenorrhea.

The role of probiotics in improving menstrual health in women with primary dysmenorrhoea: A randomized, double-blind, placebo-controlled trial (the PERIOD study).

BACKGROUND: Primary dysmenorrhea is associated with poorer quality of life; however, the causal mechanism remains unclear. A vast body of literature supports the use of oral probiotics for relief from the symptoms of endometriosis; however, to our knowledge, no study has prescribed probiotics for primary dysmenorrhea. OBJECTIVE: The aim of this study is to investigate the effects of 3-month supplementation with oral probiotics on quality of life and inflammatory markers in women with primary dysmenorrhea. DESIGN: Randomized placebo-controlled trial. METHODS: A total of 72 patients (36 patients in each arm) were randomized to receive either oral sachets containing 5 billion colony-forming units each of Lactobacillus acidophilus BCMC (BCrobes Microbial Cells) 12130, Lactobacillus casei subsp BCMC 12313, Lactobacillus lactis BCMC 12451, Bifidobacterium bifidum BCMC 02290, Bifidobacterium longum BCMC 02120, and Bifidobacterium infantis BCMC 02129 each or placebo twice daily for 3 months. Main outcome measures were visual analog scale, verbal rating scale, physical and mental health scores using Short-Form 12-Item version 2 questionnaire, frequency of nonsteroidal anti-inflammatory drug use, and changes in inflammatory markers (interleukin-6, interleukin-8, and tumor necrosis factor alpha) before and after treatment. RESULTS: There was no significant difference in the quality of life scores between the probiotic and placebo groups. Both groups showed significant improvement in pain (visual analog scale) and severity (verbal rating scale) scores but the probiotic group had much lower nonsteroidal anti-inflammatory drug use (odds ratio: 0.69, 95% confidence interval: 0.26-1.83) and better mental health scores (mean change: 6.5, p = 0.03 versus 6.1, p = 0.08) than the placebo group. There was a significant confounding effect of nonsteroidal anti-inflammatory drug use on quality of life scores. No significant difference was found in inflammatory cytokines. CONCLUSION: Tested oral probiotics improved mental health and potentially reduced the use of nonsteroidal anti-inflammatory drugs; however, there was no significant change in inflammatory markers. Further research with a larger sample size is needed to confirm the findings. REGISTRATION: This study is registered under ClinicalTrials.gov (NCT04119011).

Use of Probiotic in Primary DysmenorrhoeaThis study looked at whether taking probiotics (good bacteria) for 3 months could improve the quality of life and reduce pain in women with painful periods. The study found that probiotics did not significantly improve quality of life scores, but did reduce the use of painkillers and improve mental health scores. However, the probiotics did not have a significant effect on inflammatory markers in the body. More research is needed to confirm the findings.

Use of Vitex agnus-castus in patients with menstrual cycle disorders: a single-center retrospective longitudinal cohort study.

PURPOSE: To evaluate clinical characteristics, quality of life (QoL) and effectiveness in patients with menstrual cycle disorders (MCDs) including abnormal uterine bleeding, dysmenorrhea and mastodynia/mastalgia related to premenstrual syndrome taking the Vitex agnus-castus (VAC) products Cyclodynon® or Mastodynon® in a real-world setting. METHODS: A single-center retrospective longitudinal cohort study (3 ± 1 months), using data obtained from healthcare data archive and telephone interviews. The main study variables were changes in bleeding, menstrual pain, breast tenderness and patients' QoL. RESULTS: Data from 1700 women with a mean age of 30.2 years (± 6.3) were analyzed. The most common MCDs were dysmenorrhea (43.8%) and mastodynia/mastalgia (21.1%). Three-month treatment with VAC extract substantially decreased the percentage of patients with irregular cycle (from 9.1% to 0.1%) and breast tenderness (from 39.9% to 0.8%). Improvement in bleeding intensity, frequency and menstrual pain was experienced by 83.4%, 79.2%, and 85.2% of the patients, respectively. When analyzed by disease category, these parameters improved in almost all dysmenorrhea patients, while they improved to a lesser extent in mastodynia/mastalgia patients. QoL improved in all aspects, but was reported by a higher proportion of dysmenorrhea patients compared to mastodynia/mastalgia patients. Treatment was overall well tolerated with a favorable safety profile. CONCLUSION: These real-world data demonstrate the effectiveness of the VAC-containing products Cyclodynon® and Mastodynon® in the three-month treatment of MCDs, with a pronounced improvement in key disease symptoms and QoL. Intriguingly, while QoL was generally greatly improved, the response to VAC therapy varied depending on the type of underlying MCD.

Dysmenorrhoea: An update on primary healthcare management.

BACKGROUND: Dysmenorrhoea is the most common gynaecologic condition affecting people assigned female at birth and has significant effects on immediate and long­term quality of life. Effective treatments are widely available at low cost but often have poor uptake. There is growing evidence that a significant proportion of people with severe dysmenorrhoea will develop other persistent pain syndromes and dysmenorrhoea might be a key contributor to the development of those conditions. OBJECTIVE: The aim of this article is to provide an update on dysmenorrhoea and its management in a primary care setting, including evaluation and treatment. DISCUSSION: Treatment decisions should incorporate shared decision making and account for the preferences and goals of the patient, including fertility plans. First-line treatments include non-steroid anti-inflammatory drugs and hormonal therapies. Various non-pharmacologic therapies and lifestyle modifications can complement first-line medical therapies or be used as alternatives when medical therapies are contraindicated or declined.

Dexketoprofen versus Tenoxicam in Acute Severe Pain Due to Primary Dysmenorrhea.

OBJECTIVE: To evaluate the analgaesic efficacy of tenoxicam and dexketoprofen in patients admitted to the Emergency Medicine (EM) Clinic with severe acute pain due to primary dysmenorrhea (PD). STUDY DESIGN: Randomised-controlled trial. Place and Duration of the Study: Emergency Medicine Clinic, Health Sciences University, Adana City Training and Research Hospital, Adana, Turkiye, from January to December 2022. METHODOLOGY: Patients presenting with PD, were divided into two groups of 60 each, administered 50 mg dexketoprofen and 20 mg tenoxicam intravenously. Visual analogue scale (VAS) scores were recorded at the 15th, 30th, 60th, and 120th minutes. VAS scores and ΔVAS scores were compared with the effectiveness of drugs, the need for rescue drugs and its side-effects. RESULTS: Intravenous (IV) dexketoprofen was administered to 60 of the patients and IV tenoxicam was administered to another 60. At the time of admission, mean VAS scores of the patients were 8.8 ± 0.9 for the dexketoprofen group and 8.6 ± 0.8 for the tenoxicam group. The VAS scores of the dexketoprofen group were found to be statistically significantly lower after 30 minutes with lower need for rescue analgaesics. ΔVAS scores of the dexketoprofen group were statistically significantly higher from the 30th minute. CONCLUSION: According to the VAS scoring, IV dexketoprofen was a more effective drug than IV tenoxicam in patients who were admitted to the EM clinic with severe pain due to PD. KEY WORDS: Dexketoprofen, Primary dysmenorrhea, VAS score.

Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

Synergistic mechanism of stir-baked curcumae radix with vinegar in dysmenorrhea rats based on UPLC-Q-TOF/MS metabolomics.

Curcumae Radix (i.e. Huangsiyujin: HSYJ), a well-known traditional Chinese medicine (TCM), has been widely used in clinical practice for many years to treat depression and primary dysmenorrhea. Modern pharmacological researches have demonstrated its anti-inflammatory, antidepressant, and dysmenorrhea relief effects. According to the processing theory of TCM, it is believed that stir-baked HSYJ with vinegar may enhance the ability to disperse stagnant hepatoqi and alleviate pain. However, whether the vinegar concoction of HSYJ can enhance the therapeutic effect on the Qi stagnation due to liver depression (LDQS) type of dysmenorrhea and what its mechanism has not been well explained. Based on the processing drugs theory of "stir-baked with vinegar into liver", a metabolomic approach was used to investigate the therapeutic effect and mechanism of stir-baked HSYJ with vinegar to enhance the treatment of dysmenorrhea in rats. By establishing a rat model of dysmenorrhea of the "LDQS" type, observation of hemorheology, uterine pathological sections, COX-2 and OTR protein expression and other indicators; analysis of urinary metabolic changes in rats by UPLC-Q-TOF-MS technique, to compare the differential biomarkers and metabolic pathways in the treatment of dysmenorrhea due to "liver stagnation and qi stagnation" before and after stir-baked HSYJ with vinegar. Stir-baked HSYJ with vinegar significantly inhibited the writhing response of rats, improved hemorheology, repaired damaged diseased uterus and inhibited high expression of COX-2 and OTR proteins in uterus; 68 differential metabolites were screened from the urine of rats, compared with the raw HSYJ, the levels of 14 metabolites were significantly changed in stir-baked HSYJ with vinegar, involving the pathways of phenylalanine, tyrosine and tryptophan metabolism, cysteine and methionine metabolism, aspartate and glutamate metabolism. The potentiating effect of stir-baked HSYJ with vinegar may be related to the regulation of multiple amino acid metabolic pathways.

Unraveling the anti-primary dysmenorrhea mechanism of Ainsliaea fragrans Champ. extract by the integrative approach of network pharmacology and experimental verification.

BACKGROUND: The plant Ainsliaea fragrans Champ. (A. fragrans) named "Xingxiang Tuerfeng", is a traditional herb with a long history of therapeutic practice in southern China in the treatment of gynecological diseases. PURPOSE: The anti-inflammatory extract of Ainsliaea fragrans Champ. (AF-ext) exhibited anti-primary dysmenorrhea (PD) activity in oxytocin-induced mice. This study aimed to unravel the underlying mechanisms of AF-ext on PD by the integrative approach of network pharmacology and experimental verification. METHODS: First, the therapeutic targets of AF-ext are predicted using network pharmacology and molecular docking methods. Second, activity screening and immunoblotting methods were used for target validation. Then, the therapeutic effect of AF-ext on PD was evaluated using oxytocin-induced mice and uterine strips model. RESULTS: AF-p1, and AF-p2, the active ingredients of AF-ext, showed inhibitory effects on COX1/2 and EGFR, and all five active components showed antagonistic activity on TRPV1. AF-ext (25, 50, 100 mg/kg) could significantly reduce the number of writhing times and prolong writhing latencies in a dose-dependent manner. AF-ext inhibited spasmolytic activity in uterine strips induced by oxytocin and Ca2+ stimulation. AF-ext inhibited NF-κB/COX-2/PG pathway and activation of the NLRP3 inflammasome in PD mice. It significantly downregulated the PD-induced overexpression of p-p65/p65, p-IκBα, and COX-2 by inhibiting the NF-κB pathway. Moreover, the overexpression of NLRP3, p20/pro-Caspase 1, and p17/pro-IL-1ß was greatly downregulated. CONCLUSIONS: AF-ext demonstrated anti-inflammatory, analgesic, and spasmolytic activity in the treatment of PD. It inhibited the NF-κB/COX-2/PG pathway and NLRP3 inflammasome activation in PD mice with a multi-target approach.

Uncommon Location for a Common Disease, Simulating Cervical Cancer: A Rare Case Report.

BACKGROUND: Genital tuberculosis (GTB) is a common form of extra-pulmonary TB with cervical TB being a rare entity accounting for 0.1-0.65% of all TB cases globally. It is usually asymptomatic but may present with infertility, menstrual irregularities, dyspareunia, dysmenorrhoea, or vaginal discharge. CASE PRESENTATION: The present case report briefs about a 39 years old nulliparous infertile woman who presented with complaints of irregular menstrual cycles and amenorrhea with an erosive papillary growth over the cervix simulating invasive cervical carcinoma. Her Pap smear report revealed the presence of granulomas. On cervical punch biopsy also a large number of granulomas were seen and on Ziehl Nielsen staining the diagnosis of TB was further confirmed by the presence of acid-fast rodlike bacilli. The patient responded well to anti-tubercular drugs. DISCUSSION: GTB in most of the cases remains asymptomatic with infertility being the most common presenting complaint. Other symptoms include menstrual irregularities, amenorrhoea, dysmenorrhoea, dyspareunia, chronic pelvic pain, and occasionally abnormal vaginal discharge. Tuberculous cervicitis is difficult to diagnose clinically and many times mimics cervical malignancy. RESULT AND CONCLUSION: Hence, cervical tuberculosis should be kept in the differential diagnosis of cervical cancer especially in an infertile woman from a developing country.

Periods Shouldn't Bring Any Adolescents' World to a Full Stop. Period. An Online Survey of Adolescents' Experience of Menstruation.

STUDY OBJECTIVE: Few studies have explored what specific outcome measures contained in assessment tools for period and pelvic pain are most relevant to adolescents. Co-design is a valuable method of ensuring input from those with lived experience. The Longitudinal Study of Teenagers with Endometriosis Periods and Pelvic Pain in Australia (LongSTEPPP) Co-Design Periods Survey comprised an anonymous online survey of adolescents' experience of menstruation to inform patient-reported outcome measures for the larger 5-year project. METHODS: Adolescents aged 12-18 years whose periods had commenced at least 3 months previously and with demonstrated capacity to consent were invited to participate in an online survey. Recruitment was primarily via social media channels. RESULTS: Of the 1811 adolescents who participated, 85% reported that periods had a "moderate" or greater impact on their life. Pain (90.7%), heavy flow (56.2%), and worry about leakage (49%) were common reasons for missed activities. Menstrual symptoms were wide-ranging and included cramping, nausea, poor energy, and impacts on mood. When asked where adolescents sought assistance with their periods, 39.8% had seen their general practitioner, 21.3% their school nurse, and almost 1 in 10 had consulted a mental health practitioner (9.3%). To manage menstrual symptoms, heat packs (66.0%), over-the-counter medications (55.8%), and prescription medications (28.6%) were used. CONCLUSION: We found a lack of menstrual health awareness in adolescents. Periods had a significant effect on their lives, and adolescents commonly missed activities. In managing menstruation, a wide range of practitioners were consulted. Nearly a third were prescribed medication to manage their periods. These findings have directed the longitudinal study as to how best to capture outcome measures that reflect the impact of periods on adolescents.

Omega-3 long chain polyunsaturated fatty acids as a potential treatment for reducing dysmenorrhoea pain: Systematic literature review and meta-analysis.

AIM: This systematic literature review with meta-analysis aimed to determine the effect of omega-3 long chain polyunsaturated fatty acids on prostaglandin levels and pain severity in women with dysmenorrhoea and identify adverse side effects. METHODS: A literature search was conducted in Embase, Scopus, Web of Science, MEDLINE complete, CINAHL and AMED databases (PROSPERO CRD42022340371). Included studies provided omega-3 long chain polyunsaturated fatty acids compared to a control in women with dysmenorrhoea and reported pain and/or prostaglandin levels. A random effects meta-analysis with Cohen's d effect size (95% confidence interval) was performed in SPPS for studies that reported pain outcomes. Study quality was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. RESULTS: Twelve studies (n = 881 dysmenorrhoeal women) of predominantly neutral quality (83%) were included that provided daily supplementation of 300-1800 mg omega-3 long chain polyunsaturated fatty acids over 2 or 3 months. Meta-analysis (n = 8 studies) showed a large effect of omega-3 long chain polyunsaturated fatty acids (d = -1.020, 95% confidence interval -1.53 to -0.51) at reducing dysmenorrhoea pain. No studies measured prostaglandin levels, 86% of studies measuring analgesic use showed a reduction with omega-3 long chain polyunsaturated fatty acids and few studies reported mild adverse side effects in individual participants. CONCLUSIONS: Findings suggest that daily supplementation of 300-1800 mg omega-3 long chain polyunsaturated fatty acids over 2-3 months are generally well tolerated and reduces pain and analgesic use in women with dysmenorrhoea. However, the neutral quality of research is limited by methodological issues and the mechanism of action remains to be determined.

Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.

INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study. METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4). CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.Die primäre Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr häufig auftritt und ihre Lebensqualität beeinträchtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiemöglichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen für die Patientin verbunden. Tuina-Massage und chinesische Kräuterkompressen gelten als Formen der äußerlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kräuterkompressen kombiniert, um eine möglichst wirksame und sichere Behandlung der PD bereitzustellen.Es handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erfüllen, im Verhältnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erhält Tuina in Kombination mit chinesischen Kräuterkompressen, während die Kontrollgruppe nur eine Behandlung mit chinesischen Kräuterkompressen erhält. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal täglich, dreimal pro Menstruationszyklus). Das primäre Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekundären Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (CV4) ermittelt.Diese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kräuterkompressen zur Behandlung von PD in der Kategorie Kältekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kräuterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege für eine mögliche alternative Behandlung von PD in der Zukunft liefern wird.

Carvacrol-Loaded Nanoemulsion Promotes Tocolytic and Anti-Dysmenorrhea Effects in Rodents.

INTRODUCTION: Carvacrol is a phenolic constituent of essential oils that has antinociceptive, anti-inflammatory, and antioxidant activities. METHOD: This study aimed to evaluate the in vitro spasmolytic and in vivo anti-dysmenorrhea potential of a nanoemulsion-containing carvacrol (nanoCARV). RESULTS: In isolated rat uterus, nanoCARV reduced spontaneous contractions (pEC50 = 3.91 ± 0.25) and relaxed preparations pre-contracted with oxytocin (pEC50 = 3.78 ± 0.2), carbachol (pEC50 = 4.15 ± 0.4), prostaglandin F2α (pEC50 = 3.00 ± 0.36), and KCl (pEC50 = 3.98 ± 0.32). The investigation of the mechanism of action revealed significant differences (p < 0.05) between the pEC50 values of nanoCARV in the absence or presence of aminophylline or tetraethylammonium. In a primary dysmenorrhea model, treatment with nanoCARV reduced the number of oxytocin-induced abdominal writhes. CONCLUSIONS: These data indicate that the anti-dysmenorrhea effect of nanoCARV may be related to the relaxation of uterine smooth muscle, with participation of the cAMP signaling pathway and potassium channels.

Factors Predicting Removals of the Levonorgestrel-Releasing Intrauterine System in an Adolescent Cohort.

OBJECTIVE: Use of 52-mg levonorgestrel intrauterine system (LNG-IUS) in adolescents for heavy menstrual bleeding (HMB), dysmenorrhea, and contraception has increased, yet little is known about the factors predicting removal and dissatisfaction in adolescents. The aim of this study was to identify factors predicting LNG-IUS removal in adolescents. METHODS: This was a retrospective cohort study including all adolescents (9-19 years) who underwent LNG-IUS insertion between 2012 and 2021 (n = 536). A medical record review was conducted and data were collated on medical and gynecological history, age, indications for insertion, complications, expulsions, and removals. The data were analyzed using χ2 tests. RESULTS: Indications for LNG-IUS insertions (n = 536) among 517 individual patients (n = 517) included menstrual management (n = 142), HMB alone (n = 118), HMB and pelvic pain/dysmenorrhea (n = 105), dysmenorrhea/pelvic pain alone (n = 47), and contraception (n = 16). Associated diagnoses included intellectual disability (44.29%, 229/517), chronic pain conditions (12.77%, 66/517), and additional mental health concerns (24.37%, 126/517). Patient dissatisfaction with LNG-IUS led to removal in 61 (11.38%), mostly for pain or persistent bleeding. Higher removal rates occurred in those with associated chronic pain conditions (46.97%, χ2 = 55.9, P < .05), mental health concerns (16.67%, χ2 = 5.06, P < .05), and bleeding disorders (26.32%, χ2 = 5.09, P < .05). Among the cohort with an intellectual disability, lower rates of removal occurred (5.7%, χ2 = 11.2, P < .05). Whereas the LNG-IUS removal rate among gender-diverse youth was 23.07%, this was not statistically significant. Younger age was also not associated with a statistically significant increase in removals (13.72%, χ2 = 0.73, P > .05). DISCUSSION: Adolescents have a low dissatisfaction and removal rate (11.38%) of LNG-IUS. Chronic pain, bleeding tendency, and mental health concerns are associated with higher removal rates and intellectual disability with lower rates. These findings are useful in counselling patients and families about LNG-IUS.

Depression, anxiety, insomnia and dysmenorrhea in stressed fingolimod-treated women with multiple sclerosis.

OBJECTIVE: This study examined the prevalence and correlates of depression, anxiety, insomnia, and dysmenorrhea in stressed fingolimod-treated women with multiple sclerosis. METHODS: This cross-sectional study recruited female patients diagnosed with multiple sclerosis and high stress scores from Al-Bashir Hospital in Jordan. Depression was assessed by the Patient Health Questionnaire (PHQ-9); anxiety by the Generalized Anxiety Disorder (GAD-7) scale; insomnia by the Insomnia Severity Index (ISI-A) scale; and dysmenorrhea severity by a measure assessing working ability, location, intensity, days of pain, and miscellaneous dysmenorrhea symptoms (WaLIDD). RESULTS: A total of 129 patients were recruited for the study. Severe depression was reported in 55.8%, severe anxiety in 62.0%, severe insomnia in 36.4%, and severe dysmenorrhea in 23.3%. Multivariate analyses revealed that depressive symptoms were associated with dysmenorrhea (OR = 3.55, 95% CI = 1.56-8.12, p = 0.003); anxiety symptoms with "not using dysmenorrhea analgesics" (OR = 2.74, 95% CI = 1.16-6.46, p = 0.02) and dysmenorrhea symptoms (OR = 4.74, 95% CI = 1.94-11.59, p = 0.001); insomnia symptoms with age above 30 years (OR = 4.34, 95% CI = 1.64-11.51, p = 0.003); and dysmenorrhea symptoms with the presence of chronic diseases (OR = 4.21, 95% CI = 1.28-13.92, p = 0.02), anxiety symptoms (OR = 3.03, 95% CI = 1.18-7.73, p = 0.02), and insomnia symptoms (OR = 3.00, 95% CI = 1.18-7.64, p = 0.02). CONCLUSION: Stressed women with multiple sclerosis in Jordan experience high rates of depression, anxiety, insomnia, and dysmenorrhea. Characteristics related to these conditions may help clinicians to identify those at risk. Longitudinal studies are needed to determine the causal nature of these associations.

Patient prognosis and prediction model for taking Kampo formulas in dysmenorrhea: An observational study.

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

[Therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea in rats and its metabolomic analysis].

This study aimed to investigate the therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea(PD) and explore the underlying mechanism in conjunction with untargeted metabolomics. Forty adult female rats were randomly divi-ded into a normal group, a model control group, ibuprofen(0.12 g·kg~(-1)) group, and high-and low-dose Leonuri Herba aqueous decoction(5 and 2.5 g·kg~(-1)) groups, with eight rats in each group. The PD rat model was prepared using intramuscular injection of estradiol benzoate combined with intraperitoneal injection of pitocin. Drugs were administered by gavage from the 4th day of modeling for 7 d. After the last administration, pitocin was injected intraperitoneally, and the writhing latency and writhing times within 30 min were recorded. The uterine and ovarian coefficients were determined. Estradiol(E_2), progesterone(Prog), oxytocin(OT), cyclooxyge-nase 2(COX-2), prostaglandin E_2(PGE_2), prostaglandin F_(2α)(PGF_(2α)), and Ca~(2+) levels in uterine tissues were measured by ELISA and biochemical kits. Morphological changes in uterine and ovarian tissues were observed by hematoxylin-eosin(HE) staining. The protein expression of oxytocin receptor(OTR), prostaglandin E_2 receptor 3(EP3), and estrogen receptor alpha(ERα) in uterine tissues was detected by immunohistochemistry. The mRNA expression of OTR, PGE_2 receptors 1-4(EP1, EP2, EP3, and EP4), and PGF_(2α) receptor(FP) in uterine tissues was detected by quantitative real-time PCR. Untargeted metabolomics analysis was performed by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-QTOF-MS) technology to screen potential biomarkers and enrich metabolic pathways. The results showed that Leonuri Herba was able to significantly reduce the writhing times in PD rats(P<0.05 or P<0.01), significantly reduce the uterine and ovarian coefficients(P<0.01), and improve their histomorphology. After treatment with Leonuri Herba, PGE_2 content was significantly increased(P<0.05), COX-2, PGF_(2α) and Ca~(2+) content, and PGF_(2α)/PGE_2 was significantly decreased(P<0.05 or P<0.01), and OT content was decreased, while E_2 and Prog content tended to further increase in uterine tissues of PD rats. Correspondingly, OTR and EP3 protein expression was significantly downregulated(P<0.05 or P<0.01) and ERα protein expression was upregulated(P<0.05) in uterine tissues. The mRNA expression of FP and EP4 in uterine tissues was significantly downregulated(P<0.01), and the mRNA expression of EP1, EP3, and OTR showed a decreasing trend. The untargeted metabolomics results showed that 10 differential metabolites were restored in the plasma of PD rats after Leonuri Herba treatment. The results indicate that Leonuri Herba is effective in the prevention and treatment of PD, and the underlying mechanism may be attributed to the regulation of PGs synthesis and corresponding receptor binding.

Dysmenorrhea, intermenstrual bleeding, menstrual flow volume changes, and irregularities following COVID-19 vaccination and the association with vaccine skepticism: A retrospective observational study.

BACKGROUND: COVID-19 vaccines have provided fertile ground for research, especially with the unprecedented spread of misinformation about this disease and its vaccines. Among women, one of the most frequently reported side effects of the vaccine has been menstrual disturbance. OBJECTIVE: To investigate the perceived impact of COVID-19 vaccines on the menstrual cycle. In addition, the research seeks to identify factors that could predispose certain individuals to experience these effects, thereby contributing to a deeper understanding of the interplay between vaccines and menstrual health. DESIGN: We conducted a retrospective observational cross-sectional study. METHODS: Any woman of menstruating age who received at least one dose of the COVID-19 vaccine and currently resides in Saudi Arabia was invited to complete an online questionnaire. The questionnaire compared menstruation characteristics-regularity, volume, intermenstrual bleeding, and dysmenorrhea-before and after receiving the COVID-19 vaccine, taking into consideration possible predisposing factors such as polycystic ovarian syndrome, contraceptives, or period-blocking pills. RESULTS: Women without polycystic ovarian syndrome experienced less change in dysmenorrhea post-vaccine compared to those with polycystic ovarian syndrome (23.88% versus 37.78%, p = 0.045). Women using hormonal contraceptives were about two times more likely to experience changes in volume compared to those not using contraceptives (odds ratio = 2.09, 95% confidence interval = 1.23-3.57, p = 0.006). COVID-19 vaccine skeptics were about three times more likely to perceive changes in regularity post-vaccine compared to non-skeptics (odds ratio = 2.96, 95% confidence interval = 1.79-4.90, p < 0.001). They were also three times more likely to perceive changes in volume post-vaccine (odds ratio = 3.04, 95% confidence interval = 1.95-4.74, p < 0.001). CONCLUSION: Our data suggest significant associations between COVID-19 skepticism, the use of hormonal contraceptives, and the reported post-vaccine menstrual disturbances. This underscores the importance of public education efforts aimed at dispelling misinformation and addressing controversies related to these vaccines.