Mechanisms of electroacupuncture relieves uterine smooth muscle spasm in dysmenorrhea rats based on Rho/ROCK signaling pathway. / 基于Rho/ROCKä¿¡å·é€šè·¯æŽ¢è®¨ç”µé’ˆä»»è„‰ã€ç£è„‰ç»ç©´ç¼“è§£ç±»ç—›ç»æ¨¡åž‹å¤§é¼ å­å®«å¹³æ»‘è‚Œç—‰æŒ›çš„æœºåˆ¶.

OBJECTIVES: To investigate the effect of electroacupuncture (EA) on Rho/Rho-associated coiled-coil-forming kinases (ROCK) signaling pathway of uterus tissue in rats with dysmenorrhea, so as to explore the underlying mechanism of EA treating primary dysmenorrhea (PD) and uterine smooth muscle spasm, and to observe whether there is a difference in the effect of meridian acupoints in Conception Vessel (CV) and Governer Vessel (GV). METHODS: Sixty female SD rats were randomly divided into saline, model, CV, GV, and non-acupoint groups, with 12 rats in each group. The dysmenorrhea model was established by subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin (OT). EA (2 Hz) was applied to "Qihai" (CV6) and "Zhongji" (CV3) for CV group, "Mingmen" (GV4) and "Yaoshu" (GV2) for GV group, "non-acupoint 1" and "non-acupoint 3" on the left side for non-acupoint group, and manual acupuncture was applied to "Guanyuan" (CV4) for CV group, "Yaoyangguan" (GV3) for GV group, "non-acupoint 2" on the left side for non-acupoint group. The treatment was conducted for 20 min each time, once daily for 10 days. The writhing score was evaluated. The smooth myoelectric signals of rats' uterus in vivo were recorded by multi-channel physiological recorder. The uterine histopathological changes were observed by HE staining. The contents of prostaglandin F2α (PGF2α), OT and calcium ion (Ca2+) in uterine tissue of rats were detected by ELISA. The protein and mRNA expression levels of smooth muscle 22-α (SM22-α), RhoA and ROCKⅡ in uterine tissue were detected by Western blot and fluorescence quantitative PCR, respectively. RESULTS: Compared with the saline group, the writhing score of rats in the model group was increased (P<0.01), the amplitude voltage of uterine smooth muscle in vivo was elevated (P<0.01), the contents of PGF2α, OT and Ca2+, the protein and mRNA expression of SM22-α, RhoA and ROCK Ⅱ in uterine tissue were all increased (P<0.01). Compared with the model and the non-acupoint groups, the writhing scores of the CV and the GV groups were decreased (P<0.01, P<0.05), the amplitude voltage of uterine smooth muscle was decreased (P<0.01), the contents of PGF2α, OT and Ca2+ in uterine tissue were decreased (P<0.01, P<0.05), and the protein expression and mRNA expression of SM22-α, RhoA and ROCKⅡ in uterine tissue were decreased (P<0.01, P<0.05). HE staining showed extensive exfoliation of uterine intima with severe edema and increased glandular secretion in the model group, which was alleviated in the CV and GV groups. CONCLUSIONS: EA at acupoints of CV and GV can significantly reduce the writhing score, uterine smooth muscle amplitude voltage, pathological injury degree of uterus, and relieve spasm of uterine smooth muscle in dysmenorrhea rats, which may be related to its effect in regulating PGF2α and OT contents, inhibiting the Rho/ROCK signaling pathway, and reducing the SM22-α, RhoA, ROCKⅡ protein and mRNA expression, and Ca2+ content in uterine tissue.

Treatment of Women With Primary Dysmenorrhea With Manual Therapy and Electrotherapy Techniques: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this study was to evaluate the efficacy of electrotherapy and manual therapy for the treatment of women with primary dysmenorrhea. METHODS: Systematic searches were conducted in Scopus, Web of Science, PubMed, CINAHL, and MEDLINE. The articles must have been published in the last 10 years, had a sample exclusively of women with primary dysmenorrhea, had a randomized controlled trial design, and used interventions that included some form of manual therapy and/or electrotherapy techniques. Two reviewers independently screened articles for eligibility and extracted data. Difference in mean differences and their 95% CIs were calculated as the between-group difference in means divided by the pooled standard deviation. The I2 statistic was used to determine the degree of heterogeneity. RESULTS: Twelve selected studies evaluated interventions, with 5 evaluating electrotherapy techniques and 7 evaluating manual therapy techniques. All studies analyzed identified improvements in pain intensity and meta-analysis confirmed their strong effect. CONCLUSIONS: Manual therapy and electrotherapy are effective for the treatment of women with primary dysmenorrhea. Transcutaneous electrical nerve stimulation combined with thermotherapy and effleurage massage stands out for its effects on the intensity and duration of pain with the application of a few sessions and their long-term effects. IMPACT: Manual therapy techniques and electrotherapy methods reduce the pain intensity of women with primary dysmenorrhea. Quality of life and degree of anxiety improved significantly with manual therapy interventions. Transcutaneous electrical nerve stimulation combined with thermotherapy and effleurage massage are the interventions with which positive effects were achieved with fewer sessions.

Analysis of related factors influencing postoperative recurrence of adenomyosis treated with HIFU.

OBJECTIVE: To analyze the efficacy of high-intensity focused ultrasound (HIFU) for adenomyosis and postoperative recurrence and its influencing factors. METHODS: Clinical and follow-up data of 308 patients with adenomyosis who were treated with HIFU in Haifu Center, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from September 2017 to January 2022 were retrospectively analyzed. The recurrence of adenomyosis and the efficacy of HIFU at 6 months after surgery were followed up. To explore factors influencing postoperative prognosis and recurrence, the following variables were analyzed: patients' age, course of disease, gravidity and parity, size of the uterus, duration of HIFU, duration of irradiation, treatment intensity, dysmenorrhea score, time of follow-up, combined treatment of traditional Chinese medicine (TCM), western medicine adjuvant treatment, lesion location and type, and menorrhagia. RESULTS: Among the 308 patients, 238 (77%) were followed up from 6 to 36 months, with an average follow-up time of 15.24 ± 9.97 months. The other 70 (23%) were lost to follow-up. At 6-month after surgery, efficacy rates of dysmenorrhea and menorrhagia management were 86.7% and 89.3%, respectively. Postoperative recurrence rates were 4.8% (1-12 months), 9.0% (12-24 months), and 17.0% (24-36 months) for dysmenorrhea; and 6.3% (1-12 months), 2.4% (12-24 months), and 12.2% (24-36 months) for menorrhagia. Multivariate logistic regression analyses showed that parity (P = 0.043, OR = 1.773, 95% CI 1.018-3.087), uterine size (P = 0.019, OR = 1.004, 95% CI 1.001-1.007), combined treatment of TCM (P = 0.047, OR = 1.846, 95% CI 1.008-3.381), diffuse lesion type (P = 0.013, OR = 0.464, 95% CI 0.254-0.848) and ablation rate (P = 0.015, OR = 0.481, 95%CI 0.267-0.868) were prognostic factors (P < 0.05). Age, course of disease, gravidity, duration of HIFU, duration of irradiation, treatment intensity, preoperative dysmenorrhea score, time of follow-up, western medicine adjuvant therapy, lesion location, and preoperative menstrual volume had no effect on prognosis (P > 0.05). CONCLUSION: HIFU can effectively relieve dysmenorrhea and reduce menstrual volume in patients with adenomyosis. Parity, uterine size, lesion type (diffuse), and ablation rate are risk factors for symptom recurrence after HIFU, while the combination of TCM therapy is a protective factor for relapse. We, therefore, recommend TCM in the adjuvant setting after HIFU according to patient condition.

Acupoint application therapy alleviates pain by regulating immune function through inhibiting TLR4/MyD88/NF-κB p65 signaling in a primary dysmenorrhea rat model. / 穴位贴敷通过TLR4/MyD88/NF-κBé€šè·¯è°ƒèŠ‚åŽŸå‘æ€§ç—›ç»å¤§é¼ çš„å ç–«åŠŸèƒ½.

OBJECTIVES: To investigate the effects of graphene-based warm uterus acupoint paste on uterine Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-kappa B p65 (NF-κB p65) signaling pathway and Th1/Th2 immune balance in primary dysmenorrhea ( PD ) model rats, so as to reveal its immunological mechanisms of relieving dysmenorrhea. METHODS: Thirty SD female rats were randomly divided into 3 groups：normal group, model group and acupoint paste group, with 10 rats in each group. PD rat model was established by subcutaneous injection of estradiol benzoate for 10 consecutive days. At the same time of modeling, graphene-based warm uterus acupoint paste was applied to the acupoints of "Guanyuan" (CV4), bilateral "Zigong" (EX-CA1) and "Sanyinjiao" (SP6) of rats in the acupoint paste group. The application was continuously applied once daily for 10 d, 5 h each time. On the 11th day, oxytocin was injected intraperitoneally to observe the writhing latency, writhing times within 30 min and writhing score of rats in each group. The spleen and thymus indexes were calculated. The pathological changes of spleen and thymus tissue were observed after HE staining. The contents of serum immunoglobulin (Ig) A, IgG, tumor necrosis factor-α (TNF-α), interleukin (IL)-2, interferon-γ (IFN-γ), IL-4 and IL-10 were detected by ELISA . The protein and mRNA expression levels of TLR4, MyD88 and NF-κB p65 in rat uterine tissue were detected by Western blot and real-time quantitative PCR, respectively. RESULTS: Compared with the normal group, the writhing times and writhing scores within 30 min of rats in the model group were significantly increased(P<0.001), and the rats showed writhing reaction (P<0.01). The spleen index and thymus index were significantly decreased(P<0.01, P<0.05). The spleen and thymus had obvious pathological changes. The contents of IgA, IgG, TNF-α, IL-2 and IFN-γ in serum were significantly increased, while the contents of serum IL-4 and IL-10 were significantly decreased(P<0.001, P<0.01). The expression levels of TLR4, MyD88, NF-κB p65 protein and corresponding mRNA in uterine tissue were significantly increased(P<0.001). Following intervention, compared with the model group, the writhing latency time of rats in the acupoint paste group was prolonged, and the writhing times and writhing scores within 30 min were significantly decreased (P<0.001). The spleen index and thymus index were significantly increased(P<0.01, P<0.05). The pathological changes of spleen and thymus were improved. The contents of serum IgA, IgG, TNF-α, IL-2 and IFN-γ were significantly decreased, while the contents of IL-4 and IL-10 were significantly increased(P<0.001, P<0.05, P<0.01). The expression of TLR4, MyD88, NF-κB p65 protein and the corresponding mRNA levels in uterine tissue were decreased(P<0.001, P<0.01). CONCLUSIONS: Graphene-based warm uterus acupoint paste can regulate the immune balance of Th1/ Th2 by regulating TLR4/ MyD88/ NF-κB p65 signaling pathway, repair the pathological damage of immune tissue, improve immune function, and effectively relieve the pain symptoms of PD rats.

Clinical observation on 90 cases of primary dysmenorrhea treated by buccal acupuncture therapy: a randomized controlled study.

OBJECTIVE: To explore the short-term and long-term efficacy of buccal acupuncture therapy in the treatment of patients with primary dysmenorrhea (PD). METHODS: A total of 90 patients with PD who were admitted to the Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from January 2020 to December 2021 were included in this study and randomly divided into three groups, including the observation group, the control group, and the placebo group, with 30 patients in each group. Patients in the observation group were treated according to the syndrome types of Traditional Chinese Medicine, those in the control group were treated with Saridon, and those in the placebo group received a placebo. The visual analog scale (VAS) scores of these patients were evaluated at different time points (before treatment, 5 min after needle retention, 30 min after needle retention, 1 h after treatment, 2 h after treatment, 1 d after treatment, and 2 d after treatment). The Cox Menstrual Symptom Scale (CMSS) scores were assessed before the treatment and after three courses of treatment. Besides, these two scales were also evaluated during follow-up. Moreover, the pain score and adverse reactions of these patients were assessed during treatment. RESULTS: After treatment, the VAS and CMSS scores in the observation group decreased significantly (P < 0.05) 5 and 30 min after needle retention and after treatment. CONCLUSION: Buccal acupuncture therapy is verified to have short-term efficacy in the treatment of PD. In addition, this therapy has an immediate analgesic effect and long-term efficacy in reducing the severity and frequency of PD.

Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

Mechanisms of acupuncture for primary dysmenorrhea based on PI3K/Akt/mTOR signaling pathway in rats. / 基于PI3K/Akt/mTORä¿¡å·é€šè·¯æŽ¢è®¨ç”µé’ˆæ²»ç–—åŽŸå‘æ€§ç—›ç»å¤§é¼ çš„æœºåˆ¶.

OBJECTIVES: To observe the effect of electroacupuncture(EA) on phosphatidylinositol-3-kinases(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway of uterus tissue in rats with primary dysmenorrhea(PDM), so as to investigate its mechanisms underlying improvement of PDM. METHODS: Thirty healthy non-pregnant female SD rats were randomly divided into blank, model and EA groups, with 10 rats in each group. The PDM model was established by subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin. For rats of the EA group, EA(50 Hz, a tolerable current intensity) was applied to "Guanyuan"(CV4) and bilateral "Sanyinjiao"(SP6) for 20 min, once a day for 10 consecutive days. The number of writhing, wri-thing score, and writhing latency were observed. The uterine histopathological changes were observed by H.E. staining, and the ultrastructural changes of uterine tissue cells in each group were observed by transmission electron microscopy. The contents of prostaglandin E2(PGE2), prostaglandin F2α(PGF2α) and ratios of PGF2α/PGE2 in the serum and uterine tissue were detected by ELISA. The relative expression levels of PI3K, Akt and mTOR and their phosphorylation proteins in the uterine tissue were detected by Western blot and the ratios were calculated. RESULTS: Compared with the blank group, the number and score of writhing, latency of writhing, pathological injury score, contents of PGF2α and ratios of PGF2α/PGE2 in the serum and uterine tissue, and the levels of p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in the uterine tissue were significantly increased in the model group(P<0.01, P<0.05), while contents of PGE2 in the serum and uterine tissue were reduced(P<0.05). In comparison with the model group, the number of writhing and writhing score, pathological injury score, contents of PGF2α and ratios of PGF2α/PGE2 in both the serum and uterine tissue, the levels of p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR were obviously decreased(P<0.05, P<0.01), whereas the writhing latency was considerably prolonged in the EA group(P<0.01), with elevated contents of PGE2 in the serum and uterine tissue(P<0.05). H.E. staining showed slight dilation of uterine glandular cavity, and severe endometrial edema with extensive cell shedding and a large number of vacuole-like degeneration, apoptosis, pyknosis or fragmentation or disappearance of the nucleus, and neutrophil infiltration in the model group, which were relatively milder in the EA group. Ultrastructural results showed irregular fibroblasts of uterine tissue cells, obvious cytoplasmic edema, reduction in cytoplasmic electron density, seriously irregular nuclei, severe edema of mitochondria with dissolved matrix, fracture and disappearance of mitochondrial crests and vacuolation, and moderate dilation of rough endoplasmic reticulum in the model group, which were milder in the EA group. CONCLUSIONS: EA can improve pain and uterine inflammatory response in PDM rats, which may be associated with its functions in reducing uterine PGF2α and down-regulating PI3K/Akt/mTOR signaling.

Efficacy of manual therapy and pelvic floor exercises for pain reduction in primary dysmenorrhea: A prospective observational study.

BACKGROUND: Primary dysmenorrhea represents one of the most common causes of pelvic and low back pain. Pharmacological treatment can present some side effects, and non-pharmacological treatments should be considered to improve the symptoms of primary dysmenorrhea. The aim of this study was to evaluate the efficacy of manual therapy (MT), pelvic floor exercises (PFE), and their combination (MT + PFE) to improve clinical outcomes and pain sensitivity in women with primary dysmenorrhea. METHODS: A prospective observational study was conducted. Thirty females (age 25.0 ± 6.1 y) with history of primary dysmenorrhea participated to 8 sessions of 60 min of either MT, PFE or MT + PFE, twice per week. They participated to the different treatments according to the different services offered by the school of physiotherapy. A 0-10 numeric rating scale (NRS) was administered to assess subjective pain, while short-form 36 (SF-36) was used to evaluate quality of life. The pressure pain threshold (PPT) was assessed with a portable algometer on different pelvic and lumbar areas. RESULTS: Independently from the treatment, significant improvements were reported for general pain NRS (p < 0.001; pη2 = 0.511), as well as most the domains of the SF-36, although the general health domain did not reach statistical significance (p = 0.613; pη2 = 0.010). PPT revealed a general improvement in all tested body areas, although on the quadratus lumborum, the PFE treatment did not induce a significant improvement compared to the MT and MT + PFE protocols (p = 0.039). CONCLUSIONS: These findings highlight the importance of proposing physiotherapy treatments to females with primary dysmenorrhea to improve symptoms, with manual therapy combined with active pelvic floor exercise providing the best outcomes including an improvement of lumbar pain thresholds.

[The skin surface microcirculation of conception vessel, governor vessel and thoroughfare vessel in patients with primary dysmenorrhea].

OBJECTIVE: To observe the skin surface microcirculation of acupoints of conception vessel, governor vessel and thoroughfare vessel in patients with primary dysmenorrhea using laser speckle contrast imaging (LSCI), and provide acupoint selection basis of acupuncture-moxibustion for primary dysmenorrhea. METHODS: Ninety-nine healthy female college students with regular menstrual cycles (normal group) and 94 female college students with primary dysmenorrhea (dysmenorrhea group) were recruited. Before menstrual period, on the first day of menstruation, and on the third day after menstruation, LSCI was used to observe the surface microcirculation at the abdominal acupoints of conception vessel, i. e. Yinjiao (CV 7), Qihai (CV 6), Shimen (CV 5), Guanyuan (CV 4), Zhongji (CV 3) and Qugou (CV 2), acupoints of thoroughfare vessel, i. e. Huangshu (KI 16), Zhongzhu (KI 15), Siman (KI 14), Qixue (KI 13), Dahe (KI 12), Henggu (KI 11) and acupoints of lumbosacral region of governor vessel, i. e. Xuanshu (GV 5), Mingmen (GV 4), Yaoyangguan (GV 3), Yaoshu (GV 2) as well as two non-acupoints. RESULTS: Before menstrual period, there was no significant difference in the surface blood perfusion of the acupoints between the dysmenorrhea group and the normal group (P>0.05). On the first day of menstruation, the surface blood perfusion of Xuanshu (GV 5), Mingmen (GV 4), Yaoyangguan (GV 3) and right Huangshu (KI 16) in the dysmenorrhea group was higher than that in the normal group (P<0.05, P<0.01). On the third day after menstruation, the surface blood perfusion of the right Henggu (KI 11) in the dysmenorrhea group was lower than that in the normal group (P<0.05). CONCLUSION: In patients with primary dysmenorrhea, on the first day of menstruation, the surface blood perfusion of Xuanshu (GV 5), Mingmen (GV 4), Yaoyangguan (GV 3) of governor vessel, and the right Huangshu (KI 16) of thoroughfare vessel is increased, while on the third day after menstruation, the surface blood perfusion of the right Henggu (KI 11) of thoroughfare vessel is decreased. These findings might provide a basis for acupoint selection in the acupuncture-moxibustion treatment of primary dysmenorrhea.

Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis.

BACKGROUND: The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo response is unclear. OBJECTIVE: This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects. SEARCH STRATEGY: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were searched from inception up to August 20, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs) using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included. DATA EXTRACTION AND ANALYSIS: Pain intensity, retrospective symptom scale, and health-related quality of life were outcome measures used in these trials. Placebo response was defined as the change in the outcome of interest from baseline to endpoint. We used standardized mean difference (SMD) to estimate the effect size of the placebo response. RESULTS: Thirteen RCTs were included. The pooled placebo response size for pain intensity was the largest (SMD = -0.99; 95% confidence interval [CI], -1.31 to -0.68), followed by the retrospective symptom scale (Total frequency rating score: SMD = -0.20; 95% CI, -0.80 to -0.39. Average severity score: SMD = -0.35; 95% CI, -0.90 to -0.20) and physical component of SF-36 (SMD = 0.27; 95% CI, -0.17 to 0.72). Studies using blunt-tip needles, single-center trials, studies with a low risk of bias, studies in which patients had a longer disease course, studies in which clinicians had < 5 years of experience, and trials conducted outside Asia were more likely to have a lower placebo response. CONCLUSION: Strong placebo response and some relative factors were found in patients with primary dysmenorrhea. PROSPERO registration number: CRD42022304215. Please cite this article as: Sun CY, Xiong ZY, Sun CY, Ma PH, Liu XY, Sun CY, Xin ZY, Liu BY, Liu CZ, Yan SY. Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis. J Integr Med. 2023; 21(5): 455-463.

[Regularity of meridian-acupoint reactions of foot three yin meridians in primary dysmenorrhea and secondary dysmenorrhea patients].

OBJECTIVE: To observe the meridian-acupoint reactions of foot three yin meridians in primary dysmenorrhea(PD) and secondary dysmenorrhea(SD) patients, so as to summarize the rules of meridian-acupoint reaction and acupoints selection. METHODS: Thirty-five patients with PD (PD group), 34 patients with SD (SD group) and 35 healthy subjects (healthy group) were recruited. The compression method was used to examine the lower leg segment of the foot three yin meridians. Positive reactions(palpable skin changes, including cords, nodules, depressions) and tenderness of meridians and acupoints were recorded. The visual analogue scale (VAS) was used to evaluate the tenderness severity of acupoints. RESULTS: Compared with the healthy group, the probability of positive reactions and tenderness in foot three yin meridians were higher in PD and SD groups (P<0.01,P<0.05). Compared with the PD group, the probability of positive reactions in Spleen and Liver Meridians were higher in the SD group, with higher probability of tenderness in Liver Meridian(P<0.05). The probability of positive reactions and tenderness in the Spleen Meridian of PD and SD groups was significantly higher than that in the Kidney Meridian (P<0.01), while the probability of tenderness in the Spleen Meridian of the PD group was significantly higher than that in the Liver Meridian (P<0.05). Positive reactions and tenderness were concentrated at Yinlingquan (SP9), Diji (SP8) and Sanyinjiao (SP6) of Spleen Meridian and Xiguan (LR7) and Ligou (LR5) in Liver Meridian of PD and SD groups. In comparison with the PD group, the probability of positive reactions, tenderness and VAS score of SP8 and LR5 of the SD group were higher (P<0.05, P<0.01). CONCLUSION: The positive reaction occurs most frequently in the Spleen Meridian, followed by the Liver Meridian, and least frequently in the Kidney Meridian. The acupoints with positive reaction are different between PD and SD, which suggests that the Spleen Meridian acupoints should be the main acupoints when treating the two kinds of dysmenorrhea, and acupoints should also be selected according to the meridian and acupoint examination results.

Acupuncture and moxibustion for endometriosis: A systematic review and analysis.

OBJECTIVES: This study aimed to examine the effect of acupuncture on symptoms and health-related quality of life in patients with endometriosis. METHODS: Nine biomedical databases were searched to April 2022 to identify randomized controlled trials of acupuncture and/or moxibustion used alone or as adjunct to guideline-recommended pharmacotherapy for the treatment of endometriosis. One reviewer extracted data and another verified the data. A random effects model was used to calculate mean differences. RESULTS: Fifteen trials involving 1018 patients met the inclusion criteria, but diversity in comparisons and outcome measures prevented meta-analysis. Compared to sham acupuncture, manual acupuncture was more effective at reducing dysmenorrhea VAS pain score (mean difference [MD] - 2.40, 95 % CI [- 2.80, - 2.00]; moderate certainty evidence), pelvic pain VAS score (MD - 2.65, 95 % CI [- 3.40, - 1.90]; high certainty evidence) and dyspareunia VAS scores (MD - 2.88, [- 3.83, - 1.93]), lessened the size of ovarian cyst (MD - 3.88, 95 % CI [- 7.06, - 0.70]), and improved quality of life. Compared to conventional therapy, manual acupuncture plus conventional therapy and warm needle alone resulted in greater improvements in quality of life than conventional therapy. Among the six studies that reported safety, fewer adverse events were reported in participants who received acupuncture or moxibustion. CONCLUSIONS: Low to moderate certainty evidence from single studies showed that manual acupuncture may improve pain-related symptoms and quality of life; however, there is insufficient evidence on the overall effectiveness of acupuncture and moxibustion for endometriosis.

Efficacy of psychological interventions for dysmenorrhea: a meta-analysis.

Dysmenorrhea is pelvic pain associated with menstruation and is one of the most common pain conditions among reproductive-age women. It is commonly treated with medications, complementary and alternative medicine, and self-management techniques. However, there is increased focus on psychological interventions which modify thoughts, beliefs, emotions, and behavioral responses to dysmenorrhea. This review examined the efficacy of psychological interventions on dysmenorrhea pain severity and interference. We conducted a systematic search of the literature using PsycINFO, PubMed, CINHAL, and Embase. A total of 22 studies were included; 21 examined within-group improvement (ie, within-group analysis) and 14 examined between-group improvement (ie, between-group analysis). Random-effects meta-analyses were conducted on pain severity and interference, with average effect sizes calculated using Hedges's g. Within-group analyses showed decreased pain severity and interference at post-treatment (g = 0.986 and 0.949, respectively) and first follow-up (g = 1.239 and 0.842, respectively). Between-group analyses showed decreased pain severity at post-treatment (g = 0.909) and decreased pain severity and interference at first follow-up (g = 0.964 and 0.884, respectively) compared to control groups. This review supports the efficacy of psychological interventions for dysmenorrhea, but conclusions are tempered by suboptimal methodological quality of the included studies and high heterogeneity across studies. Additional, rigorous research is needed to determine the clinical utility of psychological interventions for dysmenorrhea.

[Effects of electroacupuncture on N-methyl-D-aspartate receptor and mitogen activated protein kinase in spinal cord of rats with primary dysmenorrhea].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression levels of N-methyl-D-aspartate receptor (NMDAR), extracellular signal-regulated kinase (ERK)1/2, p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in the spinal cord of rats with primary dysmenoramia (PDM), so as to explore the underlying mechanism of EA treating PDM. METHODS: Thirty female SD rats were randomly divided into normal group, model group and EA group, with 10 rats in each group. The PDM rat model was established by subcutaneous injection of estradiol benzoate and oxytocin into the thigh. At the same time of modeling, rats in the EA group were treated with EA (50 Hz) at "Sanyinjiao" (SP36) and "Guanyuan" (CV4) once daily, 20 min each time, for 10 consecutive days. The writhing times, writhing score and writhing latency were observed within 30 min after oxytocin injection. The uterine pathological morphology was observed by HE staining, and pathological score was calculated. Serum prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2) were determined by ELISA. The protein expression levels of NMDAR, ERK1/2, p38MAPK and JNK in spinal cord were detected by Western blot. RESULTS: Compared with the normal group, the writhing times and writhing score were significantly increased (P<0.05); the endometrial epithelial cells showed vacuolar degeneration, death and hyperemia, the uterine pathological score was increased (P<0.05); the content of serum PGF2α and the ratio of PGF2α/PGE2 were significantly increased (P<0.01), while the content of serum PGE2 was significantly decreased (P<0.01); the expression levels of NMDAR, ERK1/2, p38MAPK and JNK in spinal cord were significantly increased (P<0.05, P<0.01) in the model group. Compared with the model group, the writhing times and writhing score were significantly decreased (P<0.05), the writhing latency was prolonged (P<0.05); the endometrial epithelial cells still showed vacuolar degeneration, death and hyperemia, and the uterine pathological score was decreased (P<0.01); the content of serum PGF2α and the ratio of PGF2α/PGE2 were significantly decreased (P<0.01), while the content of serum PGE2 was significantly increased (P<0.01); the protein expression levels of ERK1/2 and JNK in spinal cord were significantly decreased (P<0.01) in the EA group. CONCLUSION: EA intervention at SP36 and GV4 has obvious analgesic effect on PDM rats, and its mechanisms may be related to reducing serum prostaglandin, alleviating uterine inflammation, and inhibiting the protein expressions of NMDAR, ERK1/2, p38 MAPK and JNK in spinal cord.

Electroacupuncture treatment of primary dysmenorrhea: A randomized, participant-blinded, sham-controlled clinical trial protocol.

BACKGROUND: Primary dysmenorrhea in women is a common and serious public health problem with psychological and physical effects. Painkillers have adverse effects, such as tolerance, addiction, irritation of the digestive tract, and liver and kidney damage. Electroacupuncture has been used as alternative therapy, although with no (non-anecdotal) evidence of effectiveness. OBJECTIVE: This study aims to provide evidence for the feasibility and efficacy of electroacupuncture in the treatment of primary dysmenorrhea. Moreover, by observing changes in serum and urine metabolites, we will evaluate the putative mechanisms mediating electroacupuncture effects in primary dysmenorrhea. METHODS: This multicenter, randomized, participant-blinded, sham-controlled clinical trial including 336 women with primary dysmenorrhea is being conducted at three hospital centers in China and consists of a 12-week treatment and a 3-month follow-up. Women will undergo electroacupuncture (n = 168) or sham acupuncture (n = 168), beginning 7 days before their menstruation, once per day, until menstruation. Each menstrual cycle equals one course of treatment, and we will evaluate a total of three courses of treatment. The primary outcome of interest is the change in visual analogue scale scores before and after treatment. The secondary outcomes include changes in the numeric rating scale, Cox Menstrual Symptom Scale, traditional Chinese medicine symptoms, the Self-Rating Anxiety Scale, Self-Rating Depression Scale, and 36-Item Short Form questionnaire scores, and a safety evaluation. Moreover, we will preliminarily investigate the metabolomics mechanism as a potential mediator of the association between electroacupuncture and primary dysmenorrhea symptomology. DISCUSSION: We aim to find a suitable non-medicinal alternative for primary dysmenorrhea treatment to reduce reliance on non-steroidal anti-inflammatory drugs. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2100054234; http://www.chictr.org.cn/.

Revealing the Central Mechanism of Acupuncture for Primary Dysmenorrhea Based on Neuroimaging: A Narrative Review.

Objective: The central mechanism of acupuncture for primary dysmenorrhea was explored by summarizing the changes in different regional networks of the brain induced by acupuncture stimulation by analyzing the existing studies. Methods: The original studies were collected and selected from three English databases such as PubMed and four Chinese databases as China Knowledge Network (CNKI). The main keyword clusters are neuroimaging, acupuncture, and primary dysmenorrhea. Results: The literature review yielded 130 possibly qualified studies, and 23 articles fulfilled the criteria for inclusion. Regarding the type of acupuncture studies, 6 moxibustion studies and 17 manual acupuncture studies for primary dysmenorrhea were included. Based on functional magnetic resonance imaging (fMRI), perfusion-weighted imaging (PWI), and positron emission tomography-computer tomography techniques (PET-CT), one or more analysis methods such as amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC), and independent components analysis (ICA) were used. The results are summarized. To summarize the high-frequency brain area alterations observed in patients with acupuncture-induced primary dysmenorrhea were the anterior cingulate gyrus, thalamus, insula, precentral gyrus, middle frontal gyrus, postcentral gyrus, putamen, and cerebellum. Conclusion: The results suggest that the mechanism of acupuncture in the treatment of primary dysmenorrhea is the involvement of networks regulating different areas of the brain in the analgesic effects of acupuncture. The brain regions involved in primary dysmenorrhea acupuncture analgesia were mainly located in the pain matrix, default mode network, salience network, and limbic system.

[Effect of electroacupuncture intervention on relieving pain and inflammation by suppressing TLR4/NF-κB signaling in rats with primary dysmenorrhea].

OBJECTIVE: To investigate the mechanism of electroacupuncture(EA) intervention in rats with primary dysmenorrhea(PDM) based on the Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB signaling pathway. METHODS: Forty female SD rats were randomly divided into blank control, model, EA and medication groups, with 10 rats in each group. PDM rat model was established by subcutaneous injection of estradiol benzoate combined with intraperitoneal injection of oxytocin. At the same time of model procedures, EA(50 Hz, dense wave) was applied to "Guanyuan" (CV4) and bilateral "Sanyinjiao" (SP6) of rats in the EA group, with needles retained for 20 min, for 10 consecutive days. Rats in the medication group received ibuprofen(125 mg/100 mL, 0.8 mL) by gavage for 10 consecutive days. At the 11th day, writhing behavior of rats was assessed. Uterine morphology was observed by eyes and uterine pathological changes were observed after HE staining. Content of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) in serum and uterine tissues was detected by ELISA; NF-κB p65 positive expression in nucleus was detected by immunofluorescence; protein expression levels of TLR4, NF-κB p65, p-NF-κB p65 and inflammatory factors interleukin (IL) -1ß and IL-18 were detected by Western blot. RESULTS: After modeling, uterus tissues were congested and edematous, with necrosis of luminal epithelium, severe edema and extensive shedding of endometrium, nuclear pyknosis, fragmentation and disappearance, neutrophils infiltration, and slight expansion of glandular cavity, which was milder in the EA and the medication groups. Compared with the blank control group, writhing times, scores and incubation period, HE pathological scores, PGF2α contents in serum and uterine tissues, ratio of NF-κB p65 positive expression in nucleus, TLR4, NF-κB p65, p-NF-κB p65, IL-1ß and IL-18 protein expression levels in uterine tissues of rats in the model group were all significantly increased(P<0.01), while PGE2 contents in serum and uterine tissues were significantly decreased(P<0.01). Compared with the model group, writhing times and scores, HE pathological scores, PGF2α contents in serum and uterine tissues, ratio of NF-κB p65 positive expression in nucleus, TLR4, NF-κB p65, p-NF-κB p65, IL-1ß and IL-18 protein expression levels in uterine tissues of rats in the EA and medication group were all significantly decreased(P<0.01), while writhing incubation period, PGE2 contents in serum and uterine tissues were significantly increased(P<0.05, P<0.01). CONCLUSION: EA intervention could relieve inflammatory response and pain in PDM rats, which may be related to its effect in reducing TLR4 expression, inhibiting NF-κB activation and down-regulating inflammatory factors levels of IL-1ß and IL-18.

Influence of Psychological Factors in Primary Dysmenorrhea Patients on De qi: a Secondary Analysis of a Randomized Controlled Trial.

Background: De qi , the needling sensation, is important in acupuncture treatment. Almost all studies believe that deep needling and manipulation could achieve a significant de qi sensation. However, relatively few studies have examined the effect of psychological factors on de qi, and those that did often reached different conclusions. Objectives: To explore the influence of psychologic factors on de qi in patients with primary dysmenorrhea (PD). Methods: Sixty-eight PD patients with cold and dampness stagnation were randomly allocated to de qi (deep insertion using thick needles, with manipulation, n=17) and non-de qi groups (shallow insertion using thin needles, without manipulation, n=51). Both groups received bilateral needling at Sanyinjiao (SP6) for 30 min. De qi was assessed using the Acupuncture De qi Clinical Assessment Scale (ADCAS). The patients' acupuncture-related anxiety and their expectations of the relationship between needle sensation and curative effect were evaluated using a five-point and four-point scale, respectively. Results: Within the de qi group, all patients experienced the de qi sensation, although anxiety levels were unrelated to de qi. Patients' expectations correlated negatively with de qi timing, and positively with electric sensation. Within the non-de qi group, 59.5% of patients experienced de qi. Between those who experienced it and those who did not, no significant differences were found in anxiety levels, although patients' expectations differed significantly. Among patients who experienced de qi sensations in the non-de qi group, anxiety and throbbing were positively correlated. Additionally, patients' expectations correlated positively with de qi intensity, as well as coldness, and numbness. Conclusion: Psychological factors should be considered when studying de qi since PD patients' expectations could influence the de qi sensation at SP6.