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.

Paeonol alleviates primary dysmenorrhea in mice via activating CB2R in the uterus.

BACKGROUND AND PURPOSE: Primary dysmenorrhea is the most common gynaecologic problem in menstruating women and is characterized by spasmodic uterine contraction and pain symptoms associated with inflammatory disturbances. Paeonol is an active phytochemical component that has shown anti-inflammatory and analgesic effects in several animal models. The aim of this study was to explore whether paeonol is effective against dysmenorrhea and to investigate the potential mechanism of cannabinoid receptor signalling. EXPERIMENTAL APPROACH: Dysmenorrhea was established by injecting oestradiol benzoate into female mice. The effects of paeonol on writhing time and latency, uterine pathology and inflammatory mediators were explored. Isolated uterine smooth muscle was used to evaluate the direct effect of paeonol on uterine contraction. KEY RESULTS: The oral administration of paeonol reduced dysmenorrhea pain and PGE2 and TNF-α expression in the uterine tissues of mice, and paeonol was found to be distributed in lesions of the uterus. Paeonol almost completely inhibited oxytocin-, high potassium- and Ca2+-induced contractions in isolated uteri. Antagonists of CB2R (AM630) and the MAPK pathway (U0126), but not of CB1R (AM251), reversed the inhibitory effect of paeonol on uterine contraction. Paeonol significantly blocked L-type Ca2+ channels and calcium influx in uterine smooth muscle cells via CB2R. Molecular docking results showed that paeonol fits well with the binding site of CB2R. CONCLUSIONS AND IMPLICATIONS: Paeonol partially acts through CB2R to restrain calcium influx and uterine contraction to alleviate dysmenorrhea in mice. These results suggest that paeonol has therapeutic potential for the treatment of dysmenorrhea.

An experimental study of the anti-dysmenorrhea effect of Chinese herbal medicines used in Jin Gui Yao Lue.

ETHNOPHARMACOLOGICAL RELEVANCE: Dang-Gui-Shao-Yao-San () and Gui-Zhi-Fu-Ling-Tang () and among the herbal medicines commonly used to treat primary dysmenorrhea with proven record of effectiveness. AIM OF THIS STUDY: This study aims to assess the effectiveness of herbal medicines on relieving primary dysmenorrhea in a murine model and to delineate a plausible mechanism. MATERIALS AND METHODS: Herbal medicines in the form of pills (Wan) or capsules, including Gui-Zhi-Fu-Ling capsule, Gui-Zhi-Fu-Ling-Wan, Jia-Wei-Xiao-Yao-Wan, and Shao-Fu-Zhu-Yu capsule were purchased from local drug stores in Nanjing. Dang-Gui-Shao-Yao-San filled from a local hospital. The identity of the drugs was validated by HPLC profiling. Female ICR mice were used for an induced dysmenorrhea model. The severity of dysmenorrhea was evaluated and scored, the motor coordination and balance affected by induced dysmenorrhea was assessed by a Rotarod test. Uterine inflammation and edema were examined after histological and immunohistochemical staining. The effect of the drugs on COX2 activity was evaluated enzymatically. RESULTS: The Chinese herbal medicines at dosages relevant to recommended uses in humans relieved painful responses, including abdominal wall contraction, pelvic twisting and/or rear limb stretching. The treatment also improved motor coordination, extending the time staying on a rotating rod from 2.64 ±â€¯0.38 min of oxytocin-induced group to 8.59 ±â€¯1.45 (DGSYs), 9.50 ±â€¯1.47 (GZFLc), 8.04 ±â€¯1.87 (GZFLw), 9.91 ±â€¯1.62 (JWXYw), and 8.20 ±â€¯1.35 min (SFZYc), respectively. H&E staining showed that treatment with ibuprofen or Chinese herbal medicines markedly decreased edema and inflammatory cell infiltration in uterine tissues. The treatment did not significantly affect pattern of COX2 staining. In an in vitro enzymatic assay, the Chinese herbal medicines showed strong inhibitory activity against cyclooxygenase-2. The aqueous extracts from P. lactiflora or P. suffruticosa, two of the common components in the formulae tested, also showed anti-dysmenorrhea activity in the rotarod assay. CONCLUSION: The study demonstrates that traditionally used Chinese herbal medicines are effective against induced-dysmenorrhea. These herbal medicines relieve dysmenorrhea symptoms likely though inhibition of cyclooxygenase activity.

Extracts of compound Muniziqi granule suppressed uterus contraction and ameliorated oxytocin-induced primary dysmenorrhea.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Muniziqi granule (CMG) is usually used as a traditional Uighur medicine to treat acne, chloasma, skin inflammation, primary dysmenorrhea (PDM), and menopausal syndrome. However, there are no sufficient data to support the clinic uses of CMG in PDM. AIM OF THE STUDY: This work aims to examine the effect of CMG as a treatment for PDM and reveal its possible therapeutic mechanism. MATERIALS AND METHODS: In vivo and in vitro mouse PDM models were utilized in this study. The mouse uterine contraction was induced by oxytocin after progynova or estradiol benzoate pretreatment. CMG, alkaloid extracts from seeds of Peganum harmala (AEP), and 10% and 95% ethanol extracts from seeds of Nigella glandulifera (EEN10 and EEN95) were given to mice in three doses by gavage. The writhing times within 30 min after oxytocin treatment were recorded to evaluate the analgesic effect, and the glutathione peroxidase (GSH-Px), malondialdehyde (MDA), 6-keto-prostaglandin F1α (6-k-PGF1α), prostaglandin F2α (PGF2α), thromboxane B2 (TXB2), and nitric oxide (NO) levels in uterine tissues and PGF2α and MDA in serum were determined. The effects (contractile curve) of CMG, AEP, EEN10, and EEN95 on uterus contraction induced by oxytocin in isolated mouse uterus were recorded. RESULTS: In contrast to the control group, CMG, AEP, N10, and N95 could display analgesic activities dose dependently by reducing the writhing response of the PDM model mice. CMG, AEP, EEN10, and EEN95 could also remarkably decrease the level of PGF2α, 6-k-PGF1α, TXB2, NO and MDA in uterine tissues and PGF2α and MDA in serum, whereas the activity of GSH-Px in uterine tissues was increased. Furthermore, CMG, AEP, EEN10, and EEN95 could significantly inhibit the frequency and amplitude of isolated uterus induced by oxytocin in a concentration-dependent manner. CONCLUSIONS: CMG exhibited a significant protective effect on experimental PDM. The mechanisms are probably associated with abating lipid peroxidation and over-inflammatory reaction, and alleviating the contraction of isolated mouse uterus. The seeds of P. harmala and N. glandulifera in the CMG may play an important role in exerting protective effects on PDM. This study provides pre-clinic proof to the use of CMG in clinical practice of PDM.

Comparisons of pharmacokinetic and tissue distribution profile of four major bioactive components after oral administration of Xiang-Fu-Si-Wu Decoction effective fraction in normal and dysmenorrheal symptom rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiang-Fu-Si-Wu Decoction (XFSWD) has been widely used to treat primary dysmenorrhea in clinical practice for hundreds of years and shown great efficacy. One fraction of XFSWD, which was an elution product by macroporous adsorption resin from aqueous extract solution with 60% ethanol (XFSWE), showed great analgesic effect. The present study was conducted to investigate the possible pharmacokinetic and tissue distribution profiles of four major bioactive constituents (berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine) after oral administration of XFSWE in dysmenorrheal symptom rats, and to compare the difference between normal and dysmenorrheal symptom rats. MATERIALS AND METHODS: Estradiol benzoate and oxytocin were used to produce dysmenorrheal symptom rat model. The experimental period was seven days. At the final day of experimental period, both normal and dysmenorrheal symptom rats were orally administrated with XFSWE, and then the blood and tissues samples were collected at different time points. Berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine in blood and tissue samples were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data using non-compartmental methods. The differences of pharmacokinetic parameters among groups were tested by one-way analysis of variance (ANOVA). RESULTS: There were statistically significant differences (P<0.05) in Cmax, Tmax, AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and CL/F between normal and dysmenorrheal symptom rats that orally administered with same dosage of XFSWE. In tissue distribution study, the results showed that the overall trend was C(Spleen)>C(Liver)>C(Kidney)>C(Uterus)>C(Heart)>C(Lung)>C(Ovary)>C(Brain)>C(Thymus), C(M-60 min)>C(M-120 min)>C(M-30 min)>C(C-60 min)>C(C-120 min)>C(C-30 min). The contents of protopine in liver, spleen and uterus were more than that in other tissues of dysmenorrheal symptom rats. Compared to normal rats, partial contents of the compounds in dysmenorrheal symptom rats׳ tissues at different time points had significant difference (P<0.05). CONCLUSIONS: This study was the first report about pharmacokinetic and tissue distribution investigation in dysmenorrheal symptom animals. The results indicated that berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine have higher uptake and slower elimination in the rats with dysmenorrheal syndrome, which suggests that the rate and extent of drug metabolism were altered in dysmenorrheal syndrome rats. And the results also demonstrated that berberine, protopine and tetrahydropalmatine in normal and dysmenorrheal symptom rats had obvious differences in some organs and time points, suggesting that the blood flow and perfusion rate of the organ were altered in dysmenorrheal symptom animals.

Plasma metabolic profiling of normal and dysmenorrhea syndrome rats and the effects of Xiang-Fu-Si-Wu Decoction intervention.

CONTEXT: Primary dysmenorrhea (PDM), a common, clinically heterogeneous endocrine disorder affecting young women, is associated with endocrinopathy and metabolic abnormalities. The Xiang-Fu-Si-Wu Decoction (XFSWD) is a traditional Chinese medicine preparation used to treat PDM. OBJECTIVE: In the current study, a plasma metabonomics method based on the ultra-high-performance liquid chromatography-quantitative time-of-flight-mass spectrometry (UHPLC-Q-TOF-MS) system was employed to examine the mechanism of XFSWD action in PDM. MATERIALS AND METHODS: Estradiol benzoate (0.01 g/kg/d) and oxytocin (5 mL/kg) were used to create the dysmenorrhea rat model. Based on the chromatographic data of plasma samples at different time-points following oral administration of XFSWD mixed in water (37.8 g crude herbs/kg) on day 7, partial least square (PLS) and discriminate analysis (DA) were applied to visualize group differentiation and marker selection. RESULTS: Systemic changes occurring in PDM reflect alterations in not only uterus function but also whole-body metabolism. The XFSWD was effective as a therapeutic agent for PDM by reflect metabolic pathway. Prostaglandins and lysophospholipids were identified as two marker types for oxytocin-induced dysmenorrhea syndrome, including LysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0), PGJ2, 11-deoxy-11-methylene-PGD2, 15-deoxy-δ-12,14-PGJ2, LysoPC(20:3), etc. Specifically, the concentrations of prostaglandins compounds (PGJ2, 11-deoxy-11-methylene-PGD2, 15-deoxy-δ-12,14-PGJ2) were increased while those of lysophospholipid compounds [lysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0)] were decreased to a significant extent (p < 0.05) in dysmenorrheal rats. Upon treatment with the XFSWD at 12 h, the concentrations of lysophospholipids showed no significant differences (P > 0.05) between the model and normal groups. The lysophospholipid levels were restored. Lysophospholipids were the key factors in phospholipid metabolism. Thus, disruption of phospholipids metabolism appears critical for the development of dysmenorrhea. The XFSWD exerted its effects by interfering with the sphingolipid metabolic pathway. DISCUSSION AND CONCLUSIONS: The metabonomics method presents a promising tool to treat PDM in animal models, and may be applicable for clinical treatment of the human disease in the future.

Evaluation of the anti-inflammatory and analgesic properties of individual and combined extracts from Commiphora myrrha, and Boswellia carterii.

AIM OF THE STUDY: The Chinese herbs of myrrh and frankincense are often combined for treating some inflammatory pain diseases with synergistic therapeutic effects. In this study, we investigated the effects of individual herbal extracts and combined extract on anti-inflammatory and analgesic activities in vivo and analyzed the potential bioactive components from the combination extract by ultra-performance liquid chromatography coupled with mass spectrum (UPLC-MS/MS). MATERIALS AND METHODS: The anti-inflammatory activities were investigated by utilizing the paw edema mice induced by formalin and carrageenan. In addition, we determined the levels of PGE(2) and nitrite in the edema paw. The analgesic activity was examined against oxytocin-induced dysmenorrhea in mice. The effects of the administration of dolantin or indomethacin were also studied for references. The components in combination extract (CWE) were analyzed by UPLC-MS/MS. RESULTS: The results showed that myrrh water extract (MWE) and the combined extract (CWE) at the 3.9 g/kg, and 5.2 g/kg showed inhibition of formalin-induced paw edema with inhibition rate of 30.44%, and 23.50%, respectively. The PGE(2) production was inhibited significantly by all samples (P<0.01 or P<0.05). CWE showed stronger suppression on carrageenan-induced mice paw edema at 2 and 3h after administration of drugs. The inhibitory effect of CWE on nitrite production was between that of MWE and water extract of frankincense (FWE) at 5.2 g/kg. The dysmenorrhea mice test showed MWE could remarkably reduce the writhing times (P<0.05) and prolong the latency period, while FWE showed no obvious effects on the writhing times. CWE significantly reduced the writhing times and prolong the latency period (P<0.01). CONCLUSION: These results demonstrated MWE, FWE, and CWE exhibited significant anti-inflammatory and analgesic activities. The findings suggest that CWE may be therapeutically more useful for mitigating inflammatory pain than individual herbal extract. In addition, 12 potential active compounds were identified from CWE. These data may support the fact the traditional application of this combined extract in treating various diseases associated with inflammatory pain.

Adverse effects of phytoestrogens on reproductive health: a report of three cases.

BACKGROUND: Phytoestrogens have been thought to have favorable effects on women's health and perhaps in offsetting cancers. The possible adverse effects of phytoestrogens have not been evaluated. CASES: Abnormal uterine bleeding with endometrial pathology in three women was found to be related to a high intake of soy products. The first woman had postmenopausal bleeding with uterine polyp, proliferative endometrium and a growing leiomyoma. The second woman presented with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyoma not responding to treatment. The third woman with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyomata presented with secondary infertility. All three women improved after withdrawal of soy from their diet. CONCLUSION: Additional information on phytoestrogens is necessary to ascertain their safety before they can be routinely used as supplements.

[Effect of acupuncture on Cx43 knock-out mice dysmenorrhea response].

OBJECTIVE: To observe the effect of acupuncture on dysmenorrhea response of Cx43 knock out mice. METHODS: Two-months-old heterozygote [Cx43(+/-)] type and wild type [Cx43(+/+)] female mice (20 mice/type) were allocated into normal group, model group, acupuncture group and Yimucao Gao (Extractum Leonuri Inspissatum) group randomly. Dysmenorrheal model was established by feeding the mouse with diethylstilbestrol (2 mg/g) once daily for 12 days. Ocytocin (i. p. 2 U/kg) was injected on the 12th day 1 h later after the feeding. Acupuncture of "Sanyinjiao" (SP 6) and "Diji" (SP 8) was given to mice of acupuncture group, once daily for 5 days from the 7th day on after modeling. The latency of body-writhing and the writhing number were measured. Ocytocin receptor (Oct-R) mRNA and vasopressin receptor (Vas-R) mRNA expression in the uterus tissue was detected by using reverse transcription polymerase chain reaction (RT-PCR) technique, and Oct-R expression was detected with immunohistochemistry after fixating and sectioning the uterus tissue. RESULTS: In comparison with their individual normal group, the latency of body-writhing of model groups in Cx43 (+/+) and Cx43 (+/-) mice shortened considerably, while the writhing number increased significantly (P<0.01). Compared with the corresponding model group, the writhing latencies of acupuncture and Yimucao Gao groups in Cx43 (+/+) mice and that of Yimucao Gao group in Cx43 (+/-) mice increased remarkably, and the writhing numbers of acupuncture and Yimucao Gao groups in Cx43 (+/+) mice and that of Yimucao Gao group in Cx43 (+/-) mice reduced markedly (P<0.05). In Cx43 (+/+) and Cx43 (+/-) mice, compared with their individual normal group, Oct-R and Vas-R mRNA expressions and Oct-R expression in model group were upregulated obviously (P<0.05). Compared with the corresponding model group, Oct-R and Vas-R mRNA expressions and Oct-R expression of acupuncture and Yimucao Gao groups in Cx43 (+/+) mice, and those of Yimucao Gao group in Cx43 (+/-) mice were down-regulated significantly (P<0.05). No significant differences were found between acupuncture and corresponding model groups in Cx43 (+/-) mice in the above-mentioned indexes (P>0.05). CONCLUSION: Acupuncture can inhibit diethylstilbestrol + ocytocin induced body writhing response in Cx43 (+/+) mice rather than in Cx43 (+/-) mice, which is closely related to its effects in down-regulating Oct-R mRNA, Vas-R mRNA and Oct-R expression.