Irregular menstruation, a common gynecological disease, mainly refers to the syndrome of abnormal menstrual cycle or menstrual period, which is more common in adolescent or menopausal women.[1,2] The typical symptoms of irregular menstruation is early or unbalanced menstrual cycle, increased or decreased amount of menstruation, or prolonged menstrual period. The symptoms can last for several months, which makes the patient weak and emaciated, or suffer from neurasthenic symptoms such as palpitation and vertigo.
The etiology and pathogenesis of irregular menstruation are complex. The clear etiology is the endocrine dysfunction of reproductive nerve to cause abnormal uterine bleeding. Insufficient progesterone secretion or premature decline of corpus luteum in corpus luteum stage could lead to poor endometrial secretion reaction, or the prolonged corpus luteum atrophy cycle may result in irregular shedding of endometrium. In modern medicine, the mostly used therapy is hormone.[3–5] Although it has obvious therapeutic effect in the short term, repeated use of sex hormone therapy often has more side effects and higher recurrence rate.
Acupuncture therapy has been widely used in the treatment of female gynecological diseases in recent years. Acupuncture could promote the recovery of menstrual cycle through acupoint selection and manipulation. The implementation of acupuncture artificial cycle therapy according to the change of female menstrual cycle can achieve remarkable results.[6–8] Modern studies have confirmed that stimulating relevant acupoints can regulate the function of hypothalamic pituitary adrenal axis and promote the development and secretion of follicles to improve the level of sex hormones.
However, there are various acupuncture therapy applied for patients with irregular menstruation, such as filiform needles, electroacupuncture, scalp acupuncture, and acupuncture combined with medications, and the efficacy are different in many studies. A network meta-analysis could be feasible to assess the efficacy and safety of various acupuncture for irregular menstruation. Therefore, we try to conduct a Bayesian network meta-analysis to evaluate the efficacy and safety of various acupuncture in the treatment of irregular menstruation.
This protocol of Bayesian network meta-analysis is drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols. The protocol has been registered in OSF Registration(10.17605/OSF.IO/4NURY). Ethics approval is not applicable in the study.
2.1 Eligible criteria
2.1.1 Type of studies
Randomized controlled trials (RCTs) of acupuncture in the treatment of irregular menstruation will be included, and languages are limited to Chinese and English. Studies with unsatisfactory outcome indicators, unable to extracting data, incorrect random methods will be excluded.
2.1.2 Type of participants
All the included cases conform to the diagnosis of irregular menstruation, regardless of nationality, race, age, gender, and source of cases.
2.1.3 Type of interventions
The study focuses on RCTs of irregular menstruation treated by any acupuncture therapies, including filiform acupuncture, fire needle acupuncture, electro-acupuncture, acupoint injection, and auricular acupuncture, with completely and precisely described point prescriptions. The intervention in the control group will not be limited.
2.1.4 Type of outcome measures
The primary outcome is the efficacy of irregular menstruation, and the secondary outcomes include serum estradiol 2, progesterone, follicular estrogen, luteinizing hormone, endometrial thickness, and the incidences of adverse events related to the interventions, such as allergy, infection, coughing, and nausea.
2.2 Literature sources and search strategy
A comprehensive literature search will be conducted in both English and Chinese database, including Medline, PubMed, Embase, Cochrane Library, Wanfang, China National Knowledge Infrastructure, Chongqing VIP Database, and Chinese Biological and Medical database, from inception to October 2021. MeSH terms and key words will be used to identify RCTs of acupuncture against irregular menstruation, with the following terms and combinations: “irregular menstruation,” “menstruation disturbances,” “menstrual irregularities,” “irregular menses” “electroacupuncture,” “acupuncture,” “acupoint injection,” “auricular acupuncture,” “fire needle acupuncture,” etc. The search strategy of PubMed is listed in Table 1.
Table 1 -
Search strategy in PubMed.
||Randomized controlled trial [Publication Type]
||Controlled clinical trial [MeSH Terms] OR Randomized [Title/Abstract] OR Clinical trials as topic [MeSH Terms] OR Randomized controlled trial [Title/Abstract] OR Random allocation [MeSH Terms]
||#1 OR #2
||Irregular menstruation [MeSH Terms]
||Menstruation disturbances [Title/Abstract] OR menstrual irregularities [Title/Abstract] OR irregular menses OR Hypomenorrhea [Title/Abstract] OR Polymenorrhea [Title/Abstract] OR Menstruation Disorder[Title/Abstract]
||#4 OR #5
||Acupuncture therapy [MeSH Terms]
||Acupuncture [MeSH Terms]
||Acupuncture therapy [Title/Abstract] OR Acupuncture [Title/Abstract] OR Acupoints [Title/Abstract] OR Acupuncture [Title/Abstract] OR Filiform acupuncture [Title/Abstract] OR Fire needle acupuncture [Title/Abstract] OR Manual acupuncture [Title/Abstract] OR Auricular acupuncture [Title/Abstract] OR Ear acupuncture [Title/Abstract] OR Electroacupuncture [Title/Abstract] OR Fire needle [Title/Abstract] OR Scalp needle [Title/Abstract] OR Abdominal acupuncture [Title/Abstract] OR Transcutaneous electrical stimulation [Title/Abstract] OR Acupoint injection [Title/Abstract]
||#7 OR #8 OR #9
||#3 AND #6 AND #10
2.3 Literature screen and data extraction
The study screen process will follow the preferred reporting items for systematic reviews and meta-analyses guidelines (Fig. 1). Endnote X9 will be applied to remove duplicate. Two authors will independently read the titles, abstracts, and full text, and screen the literature according to the eligible criteria. Then the two researchers will crosscheck the included literature. For documents that are difficult to determine, the decision will be made by discussion. Finally, literature title, first author, journal, publication year, participants’ age, sample size, sex ratio, randomization, concealment, types of interventions, outcomes, adverse events from the eligible RCT studies will be extracted. Two authors will independently extract the information, and if there is any disagreement, the decision will be made by discussion.
2.4 Risk of bias assessment
The risk of bias assessment will be performed in accordance with the Cochrane Handbook, including random sequence generation, allocation concealment, blinding, integrity of outcome data, follow-up, selecting report, and other bias. The final risk of bias of studies is of bias. According to the design and implementation of original literature, the bias will be classified as high, unclear or low risk. Two independent reviewers will conduct the assessment, and third researcher will be consulted to make a final decision.
2.5 Statistical analysis
2.5.1 Pairwise meta-analysis
RevMan 5.3 software provided by the Cochrane Collaboration will be used for pairwise meta-analysis. For dichotomous variables, the odds ratio will be used as effect indicator, and mean difference for the continuous variable, with a 95% Confidence interval. Heterogeneity will be assessed by I -square (I2), and P < .1 is considered as inter-study heterogeneity. If I2 ≤50%, the fixed-effect model will be adopted; if I2 > 50%, the random-effect model will be applied, and the heterogeneity will be explored by subgroup analysis or sensitivity analysis.
2.5.2 Network meta-analysis
ADDIS 1.16.8, Open BUGS 3.2.3, and Stata 14.0 will be performed. For dichotomous data, odds ratio and 95% confidence interval will be applied. ADDIS 1.16.8 will be applied for the variance of chains by adopting convergence evaluated by potential scale reduced factor, and potential scale reduced factor closed to 1 indicating a good convergence with a high reliability results. Node spilt analysis will be used for inconsistencies between direct and indirect comparisons. When P > .05 in node spilt analysis, the consistent model will be selected; otherwise, the inconsistent model will be selected. The surface under the cumulative ranking curve will be sued for carrying out a possible range of interventions by Open BUGS 3.2.3, from 0 to 100%, and a higher surface under the cumulative ranking curve value indicating a better intervention effect.
2.5.3 Subgroup analysis
If the heterogeneity is large, a subgroup analysis will be conducted. The sensitivity analysis will be performed by a one-by-one elimination method.
2.5.4 Reporting bias
If the included studies are larger than 10, a comparison-adjusted funnel plot will be used to assess publication bias.
2.5.5 Quality evaluation
The Grading of Recommendations Assessment, Development, and Evaluation will be applied d to assess the quality of evidence, as divided in to high, moderate, low, and very low.
A normal menstrual cycle ranges from 21 to 35 days for most women. However, many women are likely to experience an irregular menstrual cycles, such as amenorrhea, oligomenorrhea, menorrhagia, prolonged menstrual bleeding, or dysmenorrhea. Mostly, irregular menstruation can be caused by an imbalance of hormones, particularly estrogen and progesterone. The ongoing irregular menstruation can make it difficult to conceive and the negative effects may influence the normal life and work of patients.
Acupuncture is often widely used to relieve pain in many studies.[10–12] It is also said that it could improve natural healing in human body. For women, acupuncture can help regulate reproductive issues.[13,14] such as an irregular menstruation. It could reduce stress, improve blood flow in the pelvic area, and thicken the endometrium to improve menstrual cycle. However, acupuncture treatments in most studies are different, including filiform needles, electroacupuncture, scalp acupuncture. Therefore, we try to conduct a Bayesian network meta-analysis to evaluate the efficacy and safety of various acupuncture in the treatment of irregular menstruation. Yet, there still might be several limitations in the protocol, including the limited literature languages, various acupoint selections to lead to bias. Subgroup analysis, if possible, will be applied to minimize it.
Data collection: Junting Wang and Heran Zhang.
Funding support: Heran Zhang.
Literature retrieval: Junting Wang and Heran Zhang.
Software operating: Heran Zhang.
Supervision: Heran Zhang.
Writing – original draft: Junting Wang and Heran Zhang.
Writing – review & editing: Heran Zhang.
. Kwak Y, Kim Y. Irregular menstruation according to occupational status. Women Health 2018;58:1135–50.
. Kwak Y, Kim Y, Baek KA. Prevalence of irregular menstruation according to socioeconomic status: a population-based nationwide cross-sectional study. PloS One 2019;14:e0214071.
. Capuzzo M, Donno V, Lam A. Polycystic ovary syndrome, amenorrhea and the diagnostic role of anti-Mullerian hormone. Minerva Endocrinol 2020;45:376–80.
. Roomruangwong C, Sirivichayakul S, Matsumoto AK, et al. Menstruation distress is strongly associated with hormone-immune-metabolic biomarkers. J Psychosom Res 2021;142:110355.
. Tranoulis A, Laios A, Pampanos A, Yannoukakos D, Loutradis D, Michala L. Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis. Fertil Steril 2018;109:708–19. e8.
. Li X, Xu H, Fang Y, et al. Acupuncture with regulating menstruation to promote pregnancy for diminished ovarian reverse: a prospective case series study. Chin Acup Moxib 2017;37:1061–5.
. She Y, Ma L, Zhu J, et al. Comparative study on skin temperature response to menstruation at acupuncture points in healthy volunteers and primary dysmenorrhea patients. J Tradit Chin Med 2017;37:220–8.
. Xu CC, Li H, Fang YG, Bai TY, Yu XH. Effect of regulating menstruation and promoting pregnancy acupuncture therapy on negative emotion in patients with premature ovarian insufficiency. Chin Acup Moxib 2021;41:279–82.
. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ (Clinical research ed) 2015;350:g7647.
. Li H, Wang B, Chen C. Acupuncture around the greater tuberosity of the femur combined with acupuncture at Xuehai acupoint alleviates the postoperative pain of elderly patients with intertrochanteric fracture. Am J Transl Res 2021;13:8372–8.
. Li JL, Rong S, Zhou Z, et al. The efficacy and safety of acupuncture for treating osteoporotic vertebral compression fracture- (OVCF-) induced pain: a systematic review and meta-analysis of randomized clinical trials. Evid Based Complement Alternat Med 2021;2021:8574621.
. Liu LY, Tian ZL, Zhu FT, et al. Systematic review and meta-analysis of acupuncture for pain management in women undergoing transvaginal oocyte retrieval. J Pain Res 2021;14:2833–49.
. Armour M, Smith CA. Treating primary dysmenorrhoea with acupuncture: a narrative review of the relationship between acupuncture ’dose’ and menstrual pain outcomes. Acupunct Med 2016;34:416–24.
. Yang M, Du T, Long H, Sun M, Liang F, Lao L. Acupuncture for menstrual migraine: a systematic review. BMJ Support Palliat Care 2020;0:1–11.