J Acupunct Res 2021;38(2):110-121

Journal of Acupuncture Research Journal homepage: http://www.e-jar.org

Review Article Efficacy Comparison of Different Acupuncture Treatments for Hot Flashes: A Systematic Review with Network Meta-Analysis Hyo Rim Jo 1, Seong Kyeong Choi 1, Won Suk Sung 1, Eun Jung Kim 1, Su Ji Choi 2, Dong Il Kim 2, Eun Ji Noh 2,*

1. Department of Acupuncture and Moxibustion, Dongguk University Bundang Oriental Hospital, Seongnam, Korea 2. Department of Obstetrics and Gynecology, Dongguk University Ilsan Oriental Hospital, Goyang, Korea

ABSTRACT Article history: The objective of this study was to conduct a systematic review and network meta-analysis to evaluate and Submitted: February 16, 2021 compare the effectiveness of various types of acupuncture for menopausal hot flashes (HF). Randomized Revised: April 19, 2021 controlled trials (RCTs) were retrieved from 8 electronic databases, and the risk of bias was evaluated for Accepted: May 14, 2021 the included studies. Pairwise meta-analysis and network meta-analysis were performed using Review Manager and R software for indirect comparison and ranking, respectively. In total, 23 RCTs (2,302 patients) were eligible for systematic review, of which 10 were included in network meta-analysis. Network meta- Keywords: analysis showed manual acupuncture (MA) had the highest probability of reducing HF frequency and acupuncture, hot flashes, severity, followed by sham acupuncture (SA), electroacupuncture, usual care, or no treatment; furthermore, hot flushes, , systematic warm acupuncture significantly improved menopause-specific quality of life compared with MA or review, network meta-analysis electroacupuncture. Compared with hormone replacement therapy, acupuncture had less efficacy in reducing HF frequency but enhanced menopause-specific quality of life. There was no significant difference between MA and SA in mitigating HF. The existing evidence showed that MA could be used for alleviating menopausal HF. However, it is recommended that more high-quality RCTs should be performed.

https://doi.org/10.13045/jar.2020.00010 ©2021 Korean Acupuncture & Moxibustion Medicine Society. This is an open access article under the CC BY- pISSN 2586-288X eISSN 2586-2898 NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction reluctant to take hormones and are concerned about HRT [5,6]. Acupuncture has been widely used to alleviate HF in Hot flashes (HF) are a predominant symptom of menopause, menopausal women. Acupuncture can reportedly prevent the characterized by a sensation of intense heat in the face, neck, hypothalamic pituitary adrenal axis from excessively affecting the or chest [1]. Approximately two thirds of postmenopausal hypothalamic pituitary ovarian axis; and can increase endogenous women reportedly suffer from HF, and in 20% or more of all opioids release, thus normalizing the function of the hypothalamic postmenopausal women HF can last for up to 15 years after natural thermoregulatory center [7,8]. menopause [2]. HF are associated with sleep disorders, depressed Reviews on acupuncture for menopausal HF, show controversy mood, poor quality of life, and underlying vascular changes that over whether acupuncture is effective. There are several reviews cause subclinical cardiovascular disease. In addition, HF are among stating that traditional acupuncture improves HF [2], or offers the most common reasons for clinical visits and major healthcare results superior to no treatment, but not superior to sham expenses for middle aged women [3]. acupuncture (SA) [9,10]. These reviews included various types therapy alone or in combination with progesterone is of acupuncture treatments, such as manual acupuncture (MA), currently the most effective treatment for HF. However, hormone electroacupuncture (EA), warm acupuncture (WA), and acupoint replacement therapy (HRT) has risks of thromboembolic catgut embedding (ACE), but did not evaluate and compare the events, cancer, and some side effects, such as breast tenderness effects of each individual acupuncture option. Thus, it is difficult and irregular bleeding [4]. For these reasons, many women are to provide clinicians with clear guidelines on what types of

*Corresponding author. Eun-Ji Noh Dongguk University Ilsan Oriental Medicine Hospital, 27, Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Korea E-mail: [email protected] ORCID: Hyo Rim Jo https://orcid.org/0000-0002-8378-3957, Seong Kyeong Choi https://orcid.org/0000-0001-7611-4360, Won Suk Sung https://orcid.org/0000-0003-0585- 9693, Eun Jung Kim https://orcid.org/0000-0002-4547-9305, Su Ji Choi https://orcid.org/0000-0002-6068-5270, Dong Il Kim https://orcid.org/0000-0002-4997-8590, Eun Ji Noh https://orcid.org/0000-0002-3111-8496 ©2021 Korean Acupuncture & Moxibustion Medicine Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). Hyo Rim Jo et al / Acupuncture for Menopausal Hot Flashes 111 acupuncture treatments are effective. Menopause-Specific Quality of Life (MENQOL), a questionnaire Increasingly, many systematic reviews use network meta-analysis with scores ranging from 0 to 6 for 29 questions [2]. to compare 3 or more treatments, even if they have not been directly compared in clinical trials. The methodology of network Study selection and data extraction meta-analysis is a quantitative synthesis of various treatments for the same indication, combining direct and indirect evidence to All searched studies were imported into Endnote X20 (ISI evaluate potentiality of treatment effect and ranking the available Research Soft, USA). After reading the titles and abstracts, studies treatments according to the effect size [11,12]. Therefore, a that were duplicates or did not meet the inclusion criteria were systematic review and network meta-analysis was conducted in excluded. The final included studies were determined by reading this study to examine the effect of acupuncture on menopausal the full text of the articles. Data extraction was performed HF and to estimate comparative effectiveness of different types of independently by 2 researchers, and discrepancies were resolved acupuncture. through discussion. Study characteristics (author and year of publication), sample size, age range, intervention, treatment Materials and Methods frequency, duration, outcomes, results, and adverse events from each of the included RCTs were extracted. For safety, all reported Search strategy adverse events were recorded regardless of the intervention.

Eight electronic databases, including PubMed, the Cochrane Risk of bias in individual studies Library, Embase, China National Knowledge Infrastructure, Korean Medical Database, Korean studies Information Service Two researchers independently conducted quality assessments System, ScienceON, and Oriental Medicine Advanced Searching using the “risk of bias” (RoB) tool of Cochrane Collaborations. The Integrated System were searched for RCTs until December 9, 2020. RoB tool evaluates 7 areas: random sequence generation, allocation In addition, the missing literature was included by reading the concealment, participant and personnel blinding, blinding of reference lists of the retrieved systemic reviews. The languages of outcome assessment, incomplete outcome data, selective reporting, the included studies were limited to English, Chinese, or Korean. and other bias. In each category, the assessment result was The keywords for searching for RCTs were as follows: categorized into “low risk,” “high risk,” and “unclear” [13]. If the (“acupuncture” OR “electroacupuncture” OR “acupressure” OR 2 researchers had a difference of opinion, the final evaluation was “moxibustion” OR “catgut embedding” OR “warm acupuncture”) conducted through mutual discussion. AND (“hot flashes” OR “hot flushes” OR “flushing”) AND (“menopausal syndrome” OR “menopause related disorder” OR Statistical synthesis “climacteric” OR “perimenopause” OR “postmenopause”) AND (“randomized controlled trial” OR “controlled clinical trial”). Pairwise meta-analysis was performed using Review Manager According to the characteristics of each databases, Chinese or (RevMan, Version 5.4, the Nordic Cochrane Center, the Cochrane Korean terms were added. Collaboration, 2020 Copenhagen, Denmark). A randomized effects model was used for each pair of interventions, using a 95% Inclusion criteria confidence interval (CI) and a standardized mean difference (SMD) for synthesizing continuous results. The heterogeneity among the Type of studies studies was measured using I2 statistics and p values. According to Randomized controlled trials (RCTs) of acupuncture treatment the Cochrane handbook, when p > 0.05 and I2 < 50% no statistical for HF in menopausal women were considered. Non RCT studies, heterogeneity is indicated [13]. including case studies, quasi RCT, experimental studies, cohort A frequentist method was adopted to perform network meta- studies, and RCTs published in the form of letters to the editor, and analysis for indirectly comparing efficacy and the ranking of conference abstracts were excluded. different acupuncture treatments, using R software (http:// www.r-project.org/; version 4.0.3). Consistency between direct Participants and indirect evidence was estimated by the z-test, and p > 0.05 The patients were diagnosed with perimenopausal or indicated inconsistency. The results of interventions were ranked postmenopausal state with HF without restrictions on age, race, through the surface under the cumulative ranking curves and this duration of condition, and the severity of symptoms. Patients with value indicated the possibility of efficacy of the intervention [14]. their menopause caused by radiation or chemotherapy and patients with cancers were excluded. Results

Intervention and Comparison Characteristics of included studies In this network meta-analysis, 4 types of acupuncture treatments were included: MA, EA, ACE, and WA. Single use of acupuncture In total, 564 studies retrieved using databases, and a further 10 treatment was considered suitable for inclusion in this network studies were added manually. There were 391 duplicate records meta-analysis. The control group included treatment with HRT, removed, after reading the article title and abstract leaving 112 SA, usual care (the use of over-the counter drugs for symptoms records. Based on full text assessments, a further 89 articles were unrelated to HF or supplements), or no treatment (wait list). excluded. There were 23 RCTs included in the systematic review, of which 10 were included in network meta-analysis (Fig. 1). Outcome measures Of the 23 included RCTs, 9 studies were performed in China The outcome measure was the reduction in frequency and [15-23], 4 from the United States [24-27], 3 from Sweden [28-30], severity of HF and quality of life. HF frequency was defined as and 1 each from Italy [31], Iran [32], Brazil [33], Australia [34], the number of HF per day, and the severity of HF was measured United Kingdom [35], Korea [36], and Denmark [37]. by the hot flash score (HFS). Quality of life was evaluated by the The total sample size of the included RCTs involved 2,302 112 J Acupunct Res 2021;38(2):110-121

Records identified through database searches (n = 564) Additional records PubMed (n = 131), Embase (n = 240), identified through other Cochrane library (n = 162), CNKI (n = 8), sources (n = 10) KMBASE (n = 5), KISS (n = 0),

Identification ScienceON (n = 18), OASIS (n = 0)

Records after duplicates removed (n = 391) Records excluded based on the titles and abstracts (n = 279) Not RCT model Animal research Screening Records screened (n = 391) Others related Not met the inclusion of intervention

Full-text articles excluded with reasons Full text articles assessed for eligibility (n = 112) (n = 89) Not RCT (n = 27)

Eligibility Duplicated publication (n = 8) Not acupuncture therapy alone (n = 13) Not targeted interventions (n = 4) Not targeted population (n = 3) Studied included in qualitative synthesis (n = 23) No relevant outcome (n = 6) Others unrelated (n = 17) Full text not obtainable (n = 11) Included Studies included in quantitative synthesis (meta

-analysis) (n = 10)

Fig. 1. Flow chart of article retrieval of selection. RCT, randomized controlled trial. Fig. 3. Risk of bias the included randomized controlled trials.

Fig. 2. Risk of bias graph. Fig. 2. Risk of bias graph. Fig. 3. Risk of bias of the included randomized controlled trials.

patients ranging from 20 to 360 patients per study, the average Assessment of risk of bias of which was 100 patients. There were 19 2-arm RCTs, whereas 4 employed a 3-arm group design. Among the 2-arm trials, Although 5 studies [15,19,28,30,32] did not report specific there were 6 trials comparing acupuncture treatment with methods of randomization, there was no high risk of bias in HRT [15,16,20-22,32], 6 trials comparing it with SA [18,24- random sequence generation. As methods of randomization in the 26,33,34], 1 trial comparing it with usual care [36], and 2 trials RCTs, 11 [18,23,25-27,31,33-35,36,37] used computer programs, 3 comparing it with no treatment [27,37]. The remaining 4 studies [16,24,29] used envelopes, 1 [20] used drawing lots, and the other evaluated a comparison between different acupuncture treatments 3 [17,21,22] used random number tables. In terms of allocation in [17,23,29,30]. Among the 3-arm trials, 1 trial investigated MA the RCTs, 7 [16,18,21,27,29,34,37] mentioned that the assignment versus HRT versus dietary supplements [31], 1 compared MA was not known to the researchers due to the management of versus SA versus no treatment [35], 1 compared EA versus MA randomization by an independent manager, which resulted in a low versus HRT [16], and 1 evaluated ACE versus EA versus HRT [19]. risk of bias in allocation concealment. Nine RCTs [19-23,32,35-37] The selection of acupuncture points in the included RCTs was had a high risk of bias in the blinding of the participants due to the diverse, and the main choices included SP 6 (Sanyinjiao), CV 4 nature of the interventions, and 4 [18,25,28,34] were assessed as a (Guanyuan), BL 23 (Shenshu), PC 6 (Neiguan), HT 8 (Shaofu), SP low risk of bias because researchers and patients were reportedly 9 (Yinlingquan), and GV 20 (Baihui). The treatment period ranged blinded to the allocated intervention. Moreover, 11 RCTs [17,24- from 3 to 48 weeks, and the average frequency of intervention was 28,31,33,34,36,37] with an independent assessor for interventions about 3 times per week. In 2 studies [19,28], the frequency was not had a low risk of blinding of outcome assessment. In terms of reported, and in 6 trials [25,28-30,33,34], the intervention was attrition bias, 2 studies [19,24] were judged to be at high risk of initially performed twice per week and then once per week. The bias because of “As treated” analysis and a large number of missing outcome measurements included the changes in frequency and data. In addition, 2 studies [15,31] had an unclear risk of attrition severity of HF, quality of life, and follicle stimulating hormone (FSH), bias because no reasons for the missing data were provided. Six (E₂), and luteinizing hormone (LH) levels (Table 1). RCTs [22,23,24,30,33,35] did not report complete results, and therefore had a high risk of reporting bias. All included RCTs appeared to be free of other sources of bias (Figs. 2 and 3). Hyo Rim Jo et al / Acupuncture for Menopausal Hot Flashes 113

Table 1. Characteristics of Included Studies.

Intervention Mean Treatment Sample size (acupuncture points) Frequency, Study ID age (y) period Outcome Results Adverse event (n) (E/C) Experimental duration (E/C) Control group (wk) group

Acupuncture

C1: HRT (Estrogen 0.3 1. E = C1 mg + medroxy C1 > C2 54.8 ± progesterone (p < 0.05) 5.2 / acetate 1.5 mg 1. Effective rate 2. E = C1 Palma 2019 24/25/ C1: 51.2 E: cutaneous MA (NR) 1×/d) 1×/d 12 2. GCS C1 > C2 [31] 23 ± 2.6 erythema (3) C2: Dietary 3. MENQOL (p < 0.05) C2: 53.0 supplement 3. E = C1 ± 6.4 (soy E > C2 isoflavones (p < 0.05) 75 mg 2×/d) HRT (Estrogen 1. Effective rate 1. total 0.625 mg 1) HF frequency 1) E = C Mohammadyari 2×/wk, 10/10 50.6 ± MA (NR) + medroxy 5 2) Palpitation 2) E = C NR 2015 [32] 40 min 2.5 progesterone 3) Perspiration 3) E = C acetate 4) Headache 4) E = C 12.5 mg 1× d) MA (BL 23, ST 36, SP 6, PC 6, HT 7, LR 1. E > C 50.2 ± 3, DU 20, RN HRT Zhang 2006 6×/wk, 1. Effective rate (p < 0.05) 33/32 2.0 / 49.0 17; BL 18, KI (Oryzanol 4 NR [15] 30 min 2. KMI 2. E > C ± 6.0 3, KI 12, BL 20 mg 3×/d) (p < 0.05) 20, RN 4 were added for yang deficiency)

MA (EX-HN1, 1×/ LI4, wk (10 HT7, PC6, wks), 47.74 ± TE5, CV12, 1. E > C 1×/2 Soares 2020 4.26 / CV6, CV4, SA (same 1. KMI (p = 0.019) 50/50 wks 48 None [33] 47.32 ± ST36, SP6, points) 2. HF frequency/d 2. E > C (until 4.81 SP9, GB34, (p < 0.01) end LR3, LU7, point), LR5, KI3, KI6, 40 min Scalp)

E: pain (6), tingling (1), bleeding or bruising (8), syncope/ presyncope (2), 2×/wk worsening symptoms SA (2 wks), 1. HFS 1. E = C (2), heat/sensitivity 55.2 ± (non MA (KI6, KI7, 1×/wk 2. HF severity/wk 2. E = C (1), 4.3 / acupuncture Ee 2016 [34] 163/164 SP6, HT6, (until 8 3. HF frequency/wk 3. E = C swelling and itching 54.8 ± points on CV4, LR3) end 4. MENQOL 4. E = C around acupuncture 4.2 abdomen, point), 5. HADS 5. E = C point (1) limbs) 20 min C: pain (1; unrelated), syncope/ presyncope (1), worsening symptoms (1), nervousness (1), essential tremor (1) 1. E = C1 = C2 2. E = C1 = C2 1. HF frequency/wk 3. E > C1 > C2 2. HF severity/wk (p = 0.07) MA (GV20, 3. MENQOL 4. E = C1 = C2 PC6, HT 7, 4. PSQI 57.2 ± C1: SA 5. E = C1 = C2 LR3, LI4, LI11, 5. BDI-II 5.2 / (proximate to 6. E = C1 = C2 KI3, SP6, 6. State-Trait Anxiety Painovich C1: 56.8 MA points) 3×/wk, 7. 12/12/9 ST36, CV17, 12 Inventory NR 2012 [35] ± 6.5 C2: No 30 min 1) E > C1 > C2 CV6, GV14, 7. 24 hours urinary cortical C2: 54.9 treatment (p = 0.04) BL15, BL18, and metabolites ± 6.4 (wait) 2) E > C1 > C2 BL20, BL23, 1) Dehydroepiandrosteone (p = 0.05) GB34, KI3) 2) Cortisol 3) E > C1 > C2 3) Total F metabolites (p = 0.03) 4) Adrenal 4) E > C1 > C2 (p = 0.09) 114 J Acupunct Res 2021;38(2):110-121

Table 1. Continued.

Intervention Mean Treatment Sample size (acupuncture points) Frequency, Study ID age (y) period Outcome Results Adverse event (n) (E/C) Experimental duration (E/C) Control group (wk) group MA (BL23, BL20, BL 15, SA 54.1 ± BL17, GV9, 1. BDI 1. E = C (non 2×/wk Venzke 2010 4.67 / GV4, SP9, SP6, 2. BAI 2. E = C 27/24 acupuncture (4 wks), 12 None [24] 52.6 ± right LU7, left 3. HFS/d 3. E = C points on back, 25 min 2.87 KI6, KI3, KI7, 4. GCS 4. E = C limbs) HT6, HT7, LR3, GV24, GB20) E: bleeding/bruising (8), discomfort (7), insomnia (2), pain (1), itchiness (1), 2×/wk twitching (1) 56.92 ± MA (5-7 1. E = C SA (non (2 wks), 1. HF frequency/d C: bleeding/bruising Nir 1.73 / points based 2. E > C 12/17 acupuncture 1×/wk 7 2. HF severity/d (1), discomfort 2007 [25] 53.71 ± on TCM (p = 0.042) points) (5 wks), 3. MENQOL (6), insomnia 4.24 diagnose) 3. E = C 20 min (2), irritability/ restlessness (3), low energy (1), flatulence (1), resentment (1), pain (1) MA (SP4, SP6, HT7, Ll11, LV2, SA (non Vincent 2007 52.0 / 2×/wk, 1. Residual HFS/d 1. E = C 51/52 KI6, LU7, PC6, acupuncture 5 None [26] 52.0 30 min 2. Residual HFS ratio 2. E = C GB34, LV3, points) CV4, GB20) E (unrelated to MA): common cold MA (ST36, 1. HFS/d 1. E > C (p < 0.0001) 51.4 ± (5), muscle pain Kim SP6, LI4, PC6, 3×/wk, 2. HF severity/d 2. E > C (p = 0.0038) 116/59 2.9 / 51.2 Usual care 4 (2), mild joint 2010 [36] HT7, HT8, 20 min 3. HF frequency/d 3. E > C (p = 0.0089) ± 3.7 pain (2), urine CV4) 4. MRS 4. E > C (p < 0.0001) glucose increased (2), headache (1), nausea (1), 1. MSQ 1) HF scale 1. 2) Day/night sweating 1) E > C (p < 0.0001) 3) General sweating 2) E > C (p = 0.0056) 4) Menopausal specific 3) E > C (p = 0.0086) sleeping problems E: more HF (1), 4) E > C (p < 0.0001) 5) Emotional symptoms tiredness and 55.3 ± 4 MA (CV3, 5) E > C (p = 0.0008) Lund No treatment 1×/wk, 6) Memory changes headache (1), 36/34 / 54.1 ± CV4, LR8, 5 6) E = C 2019 [37] (wait) 10 min 7) Physical symptoms tingling in leg (1), 5 SP9, SP6) 7) E > C (p = 0.01) 8) Urinary and vaginal urinary frequency 8) E = C symptoms (1) 9) E = C 9) Abdominal symptoms 10) E > C (p = 0.0021) 10) Skin and hair 11) E = C symptoms 12) E = C 11) Sexual symptoms 12) Tiredness 1. HF frequency/wk 2. HFS/wk 1. E > C (p < 0.001) 3. HF Related Daily 2. E > C Interference Scale (not mentioned) 4. Center for 3. E > C (p < 0.001) Epidemiologic Studies 4. E = C Depression scale 5. 5. WHQ 1) E = C 1) Depression 2) E > C (p = 0.02) 2) Anxiety 3) E = C 3) Attractiveness 4) E > C (p < 0.001) 53.8 ± 4) Somatic 5) E > C (p = 0.001) determined Avis 3.5 / No treatment 5) Memory 6) E > C (p = 0.04) 170/39 MA (NR) by 24 NR 2016 [27] 53.6 ± (wait) 6) Sexuality 7) E > C (p = 0.002) practitioner 3.6 7) Vasomotor 8) E > C (p < 0.001) 8) Sleep 6. E > C (p = 0.01) 6. PSQI 7. E = C 7. Generalized Anxiety 8. E = C Disorder 9. 8. Perceived Stress Scale 1) E > C (p = 0.07) 9. PROMIS 2) E = C 1) Anxiety 3) E > C (p = 0.002) 2) Depression 10. E = C 3) Sleep 11. E = C 10. SF-36 11. Global Quality of Life Hyo Rim Jo et al / Acupuncture for Menopausal Hot Flashes 115

Table 1. Continued.

Intervention Mean Treatment Sample size (acupuncture points) Frequency, Study ID age (y) period Outcome Results Adverse event (n) (E/C) Experimental duration (E/C) Control group (wk) group

Electroacupuncture

HRT (Nylestriol 2 mg 1× 2 wks); for post- 1. E = C 49.90 1. KMI menopause 2. E > C Zhou ± 3.80 / 3×/wk, 2. HFS 45/45 EA (SP6) add medroxy 3 (p < 0.05) None 2006 [16] 50.03 ± 30 min 3. mental symptoms progesterone 2 3. E > C 3.20 score mg 3×/d from (p < 0.01) third month for 7 d) C1: MA (the EA (BL15, upper points 2×/wk (2 1. HF frequency/d 1. E = C1, E = C2 54.5 / BL23, BL32, of BL15, BL23, wks), 1×/ 2. HF severity/d Wyon 15/13/ 2. E = C1, E = C2 C1: 53.4 HT7, SP6, BL32) wk 12 3. KMI NR 2004 [28] 15 3. E = C1, E = C2 C2: 50.9 SP9, LR3, PC6, C2: HRT (17 (10 wks), 4. VAS for general 4. E = C1, E = C2 GV20) β-estradiol 2 30 min climacteric symptom mg 1× d) 1. HFS/d 1. E = C 2. MENQOL 2. E = C EA (CV4, EX- 3. MRS 3. E = C Cao 48 ± 4 / MA (same 3×/wk, 23/27 CA1, ST25, 8 4. Serum level 4. NR 2017 [17] 48 ± 4 points) 30 min SP6) 1) E2 1) E = C 2) FSH 2) E = C 3) LH 3) E = C EA (BL15, 2×/wk (2 1. Mood scale 54.4 ± BL23, BL32, wks), 1×/ 1. E > C (p < 0.01) Sandberg MA (same 2. SCL-90 15/15 3.6 / 53.6 SP6, SP9, LR3, wk 12 2. E = C NR 2002 [29] points) 3. VAS for general ± 3.0 HT3, PC 6, (10 wks), 3. E = C climacteric symptom GV20) 30 min 1. HF frequency/d 2. KMI EA (UB 15, 2×/wk 1. E = C 3. VAS for general UB 23, UB 32, (2 wks), 2. E = C Wyon total MA (same climacteric symptom 12/12 GV 20, H7, 1×/wk 8 3. E = C NR 1995 [30] 54.0 points) 4. Sleep Dysfunction P6, LIV3, SP6, (6 wks), 4. E = C Scale SP9) 30 min 5. E = C 5. Psychological General Well-Being index 1. HFS/d 1. E > C (p = 0.0001) 2. MENQOL E: dizziness (1), 2. E > C (p = 0.0033) 3. MRS fatigue (1), severe 3. E > C (p = 0.0002) 48.7 ± 4. Serum level needling pain EA (RN4, SA (non 4. Liu 4.0 / 3×/wk, 1) E2 (4), abdominal 180/180 ST25, EX- acupuncture 8 1) E = C 2018 [18] 48.1 ± 30 min 2) FSH discomfort (1) CA1, SP6) points) 2) E = C 3.8 3) LH subcutaneous 3) E = C 4) FSH/LH ratio hematoma (2) C: 4) E > C (p = 0.0024) 5. Use of other treatment fatigue (2) 5. E = C during study

Acupoint catgut embedding

51.6 ± EG: 1×/ 1. Effective rate CG1: EA 1. E > C2 (p < 0.05) 3.3 / d, 2. KMI ACE (BL23, (same points) C1 > C2 (p < 0.05) Song C1: 49.0 30 min 3. Serum level 30/30/30 CV4, EX-CA1, CG2: HRT 8 2. E > C2 (p < 0.05) NR 2020 [19] ± 6.0 CG1: 1) E2 SP6) (Premarin C1 > C2 (p < 0.05) C2: 51.9 1×/2 d, 2) FSH 0.625 mg/d) 3. E = C1 = C2 ± 3.4 30 min 3) LH 1. Effective rate 2. Average number of days to 1. E > C (p < 0.05) effect onset 2. E > C (p < 0.01) 3. Average number of days 3. E > C (p < 0.01) until symptoms disappear 4. (all p < 0.05) HRT (Ethinyl 4. Menopausal symptom 1) E > C estradiol score 46.16 ACE (BL23, 2) E > C pentyl ether 1) Flashes and sweating Liu ± 6.14 / GV4, CV4, 3) E > C 86/80 2.5 mg 1×/wk 12 2) Irritability NR 2007 [20] 45.75 BL15, BL18, 4) E > C 1×/2 wks + 3) Dizziness and fatigue ± 5.2 SP6) 5) E > C Oryzanol 4) Vaginal dryness 5. (all p < 0.01) 25 mg 3×/d) 5) Urinary infection 1) E < C 5. Serum level 2) E < C 1) E2 3) E < C 2) FSH 6. E < C (p < 0.05) 3) LH 6. Endometrial thickness 116 J Acupunct Res 2021;38(2):110-121

Table 1. Continued.

Intervention Mean Treatment Sample size (acupuncture points) Frequency, Study ID age (y) period Outcome Results Adverse event (n) (E/C) Experimental duration (E/C) Control group (wk) group 1. Menopausal symptom score 1) Flashes and sweating 2) Parasthesia 3) Insomnia 4) Irritability 5) Depression 6) Dizziness 1. 7) Fatigue 8) E > C 8) Joint and muscle pain (p = 0.001) 9) Headache 12) E < C ACE (SP6, BL23, 10) Palpitation (p < 0.001) CV4 + BL18 11) Tingling Otherwise, E = C for Liver and HRT (Estrogen 12) Vaginal dryness 2. E > C (p > 0.05) E: redness/swelling (1) Kidney yin Chen total 53.94 1.25 ug + 13) Urinary symptoms 3. C: nausea and lethargy 33/32 deficiency, 1×/2 wks 12 2006 [21] ± 2.94 Progesterone 2. KMI 3) E > C (p < 0.05) (8), breast distention (7) ST36, BL20 0.5 mg 1×/d) 3. SF-36 8) E > C (p < 0.05) for Spleen and 1) Physical functioning Otherwise, E = C Kidney yang 2) Role physical 4. E = C (p > 0.05) deficiency) 3) Bodily pain 5. 4) General health 1) E > C (p < 0.05) 5) Vitality 2) E > C (p < 0.01) 6) Social functioning 3) E > C (p < 0.01) 7) Role emotional 8) Mental health 4. Effective rate 5. Serum level 1) E2 2) FSH 2) LH

Warm acupuncture

1. E > C (p < 0.05) 2. E > C (p < 0.05) 1. Effective rate 3. E > C (p < 0.05) 2. KMI 45.78 ± HRT 4. 3.MENQOL 12.83 / WA (SP6, CV4, (Nilestriol 1) E > C Li 2020 [22] 35/35 1×/d 4 4. Serum level NR 46.47 ± EX-CA1) 2 mg 1×/2 (p < 0.05) 1) E2 14.20 wks) 2) E > C 2) FSH (p < 0.05) 3) LH 3) E > C (p < 0.05) WA (CV4, MA (CV4, 1. E > C 1. MRS ST25, EX- ST25, EX- (p < 0.05) 2. Serum level 49.53/ CA1, SP6, CA1, SP6, 2. Xu 2017 [23] 30/30 1×/2 d 8 1) E2 NR 50.16 e.t.c., based e.t.c., based 1) E = C 2) FSH on TCM on TCM 2) E = C 3) LH diagnose) diagnose) 3) E = C

E, experimental group; C, control group; Effectiveness rate = (total points of symptom before treatment – total points of symptom after treatment)/total points of symptom before treatment × 100%. Total effective rate was calculated for the number of cured and improved cases. AE, adverse event; BAI, Beck anxiety inventory; BDI-II, Beck depression inventory-II; EA, electroacupuncture; GCS, Greene climacteric scale; HADS, hospital anxiety and depression scale; HF, hot flash; HFS, hot flash scores; HRT, hormone replacement therapy; KMI, Kupperman menopausal index; MA, manual acupuncture; MENQOL, menopause-specific quality of life questionnaire; MRS, menopause rating scale; MSQ, MenoScores questionnaire; NR, not reported; PROMIS, patient-reported outcomes measurement information system; PSQI, Pittsurgh sleep quality index; SA, Sham acupuncture; SCL-90, symptom checklist-90; SF-36, short form 36 health survey; TCM, traditional Chinese medicine; VAS, visual analog scale; WA, warm acupuncture; WHQ, women’s health questionnaire.

Systematic review showed no significant difference between MA and SA, except for 1 RCT [33]. Painovich et al [35] reported that 24 hour urinary MA cortisol and metabolites, such as dehydroepiandrostenoe, cortisol, Twelve RCTs examined the effectiveness of MA. In the 3 total F metabolites, and adrenal androgens, were significantly studies comparing MA with HRT, the 2 interventions showed lower in MA than in SA. Data of 3 RCTs which compared MA to no significant differences [31,32], whereas Zhang [15] observed usual care [36] or no treatment [27,37], showed that MA had a MA to be more effective than HRT at improving the Kupperman significantly better effect in reducing HF frequency, severity, and menopausal index (KMI) score and effective rates. Among the 6 other menopause symptoms as indicated by the Menopause Rating RCTs [24-26,33-35] which compared MA and SA, those evaluating Scale (MRS) and Meno Scores Questionnaire (Table 1). HF frequency, severity, MENQOL, and Beck Depression Inventory Hyo Rim Jo et al / Acupuncture for Menopausal Hot Flashes 117

EA the effects of WA and MA, WA significantly reduced MRS, but Six RCTs evaluated the effectiveness of EA in comparison there were no significant differences in alterations of serum E₂, with HRT, MA, and SA. Zhou et al [16] when comparing EA to FSH, and LH levels [23] (Table 1). HRT, reported the HFS and mental health symptoms score was significantly better with EA, whereas the KMI scores did not Pairwise meta-analysis significantly differ between the 2 interventions. Among the 4 RCTs comparing MA and EA [17,28-30], there were no significant Reduction in the frequency of HFs differences between the 2 groups in most outcomes. In 1 RCT Six pairwise meta-analyses were performed to evaluate the effect [32] comparing EA and SA, EA was significantly more effective in of acupuncture treatment on reducing the frequency of HF (Table terms of the HFS, MENQOL, and MRS scores, but not in terms of 2). MA showed more significant effects than usual care (1 RCT, serum levels of E₂, FSH and LH (Table 1). SMD -0.47, 95% CI -0.78 to -0.15; p = 0.004) and no treatment (1 RCT, SMD -8.61, 95% CI -9.60 to -7.61; p < 0.001). Conversely, MA ACE (1 RCT, SMD 0.81, 95% CI 0.04 to 1.59; p = 0.04) and EA (1 RCT, All 3 RCTs [19-21] assessing the effects of ACE were compared SMD 1.01, 95% CI 0.25 to 1.78; p = 0.01) reduced the frequency with HRT. The results indicated that ACE had a higher effective of HF to a greater extent than HRT. No significant difference was rate and was more effective at improving the KMI score, but noted between MA and EA, or between MA and SA. It was judged contradictory in altering the serum levels of E₂, FSH, LH, and that there was no heterogeneity between MA and SA (I2 = 0). vaginal dryness symptoms score. Liu et al [20] reported the endometrium was significantly thicker in patients treated with Reduction in the HFS HRT than in patients treated with ACE (Table 1). There were 4 pairwise meta-analyses performed to compare the HFS (Table 3). MA was more effective than usual care at improving WA the HFS (1 RCT, SMD -0.59, 95% CI -0.91 to -0.27; p = 0.0003). There were 2 RCTs that explored the effectiveness of WA, However, no significant difference was reported in others. compared with HRT [22] and MA [23] respectively. In comparison with HRT, WA was significantly more effective in terms of effective Reduction in MENQOL score rate, KMI and MENQOL scores, but less effective for beneficially Six pairwise meta-analyses were generated to investigate the altering serum levels of E₂, FSH, LH [22]. In terms of comparing improvement in MENQOL scores with different acupuncture

Table 2. Pairwise Meta-Analysis of the Frequency of Hot Flashes.

2 Comparison Number SMD (95% CI) p I

A vs B 1 -0.04 [-0.79, 0.70] 0.910 -

A vs D 1* 0.81 [0.04, 1.59] 0.040 -

A vs E 2 -0.05 [-0.26, 0.16] 0.640 0

A vs F 1* -0.47 [-0.78, -0.15] 0.004 -

A vs G 1* -8.61 [-9.60, -7.61] < 0.001 -

B vs D 1* 1.01 [0.25, 1.78] 0.010 -

*A significant result. A: manual acupuncture; B: electroacupuncture; D: hormone replacement therapy; E: sham acupuncture; F: usual care; G: no treatment.

Table 3. Pairwise Meta-Analysis of Hot Flash Score.

2 Comparison Number SMD (95% CI) p I

A vs B 1 -0.07 [-0.62, 0.49] 0.8100 -

A vs E 1 0.02 [-0.20, 0.23] 0.8800 -

A vs F 1* -0.59 [-0.91, -0.27] 0.0003 -

B vs E 1 0.15 [-0.05, 0.36] 0.1500 -

*A significant result. A: manual acupuncture; B: electroacupuncture; E: sham acupuncture; F: usual care. CI, confidence interval; SMD, standardized mean difference. 118 J Acupunct Res 2021;38(2):110-121 therapies (Table 4). MA significantly enhanced MENQOL scores 0.699, 0.785). In network meta-analysis of changes in a reduction compared with no treatment (1 RCT, SMD -0.97, 95% CI -1.89 in frequency, the inconsistency either at the global level of the to -0.05; p = 0.04). WA showed a greater significant reduction in whole network or at the local level for a specific comparison MENQOL scores compared with HRT (1 RCT, SMD -0.58, 95% CI could not be evaluated because of the small number of studies -1.06 to -0.11; p = 0.02). SA significantly improved MENQOL scores involved in each intervention. Network meta-analysis under the compared with no treatment (1 RCT, SMD -1.32, 95% CI -2.29 to inconsistency model (design by treatment interaction model) for -0.35; p = 0.008). No significant difference was reported between global inconsistency was conducted and used as the node splitting MA and EA, between MA and HRT, and between MA and SA. method for the assessment of local inconsistency. When comparing MA and SA, there was no heterogeneity (I2 = 0). Comparative results of different interventions Network meta-analysis (1) Frequency of HFs A league table was produced for the 6 interventions, including Network plot for different interventions 5 RCTs (Table 5). Compared with no treatment, the other In the network meta-analysis plot, the thickness of the line 5 interventions were significantly more effective (Table 5). shows the number of comparisons between the 2 interventions. Furthermore, HRT, MA, and SA showed a significant reduction in Network meta-analysis included 6 interventions for the frequency the frequency of HF compared with usual care, but there was no of HF (Fig. 4A), 4 interventions for the HFS (Fig. 4B), and 6 significant difference between usual care and EA (Table 5). interventions for MENQOL scores (Fig. 4C). HRT had the highest efficacy (98.9%) for reducing the frequency of HF, which was significantly better than the efficacy of the other Evaluation of statistical inconsistency 5 interventions; MA (65.1%), SA (56.4%), EA (56.1%), usual care The results of heterogeneity assessment of the HFS and (23.5%), and no treatment (0%). MENQOL scores did not show statistically significant (2) HFS heterogeneity; therefore, the consistency model was selected (p = There were 4 RCTs including 4 interventions which reported on the HFS (Table 6). The results showed that MA, SA, and EA were more effective than usual care at reducing the HFS (Table 6). Furthermore, MA had the highest efficacy (83.8%) in relieving HF severity, followed by SA (76.0%), EA (39.4%), and usual care (0%). (3) MENQOL questionnaire The network meta-analysis data from 5 RCTs involving 6 interventions showed that WA, SA, and MA significantly improved quality of life compared with no treatment (last row of Table 7). In addition, WA was more effective at improving MENQOL scores compared with HRT (SMD -0.58, 95%CI -1.06 to -0.11). WA was the most efficacious at enhancing quality of life (86.1%), followed by SA (79.3%), MA (54.7%), EA (45.0%), HRT (31.7%), and no treatment (0%). Fig. 4. (a) manual acupuncture, (b) electroacupuncture, (c) warm acupuncture, (d) hormone replacement therapy, (e) sham acupuncture, (f) usual care, (g) no treatment. The thickness of the line shows the number of comparisons between the two Safety interventions. (A) Manual acupuncture and sham acupuncture had the largest number of comparisons followed by the comparisons of manual acupuncture and Overall, 11 RCTs [16,18,21,24-26,31,33,34,36,37] including usual care. (B) Manual acupuncture and sham acupuncture, electroacupuncture and sham acupuncture were the most compared, followed by manual acupuncture usual 1,442 patients reported on the safety of interventions. Based on care. (C) The number of comparisons between manual acupuncture group and sham these studies, the therapies included were MA, EA, ACE, SA, and acupuncture is remarkably greater than other comparisons.

Table 4. Pairwise Meta-Analysis of Menopause-Specific Quality of Life Questionnaire.

2 Comparison Number SMD (95% CI) p I

A vs B 1 -0.13 [-0.68, 0.43] 0.660 -

A vs D 1 -0.25 [-0.82, 0.31] 0.380 -

A vs E 2 0.15 [-0.05, 0.35] 0.150 0

A vs G 1* -0.97 [-1.89, -0.05] 0.040 -

C vs D 1* -0.58 [-1.06, -0.11] 0.020 -

E vs G 1* -1.32 [-2.29, -0.35] 0.008 -

*A significant result. A: manual acupuncture; B: electroacupuncture; C: warm acupuncture; D: hormone replacement therapy; E: sham acupuncture; G: no treatment. CI, confidence interval; SMD, standardized mean difference. Hyo Rim Jo et al / Acupuncture for Menopausal Hot Flashes 119

Table 5. Network Meta-Analysis Comparisons of Effectiveness for Reducing the Frequency of Hot Flashes.

D

-0.82 (-1.59, -0.04)* A

-0.87 (-1.67, -0.06)* -0.05 (-0.26, 0.16) E

-0.87 (-1.62, -0.11)* -0.05 (-0.79, 0.69) 0.00 (-0.77, 0.77) B

-1.28 (-2.12, -0.44)* -0.47 (-0.78, -0.15)* -0.42 (-0.80, -0.04)* -0.42 (-1.22, 0.39) F

-9.42 (-10.69, -8.16)* -8.61 (-9.60, -7.61)* -8.56 (-9.57, -7.54)* -8.56 (-9.80, -7.32)* -8.14 (-9.19, -7.10)* G

*A significant result. A: manual acupuncture; B: electroacupuncture; D: hormone replacement therapy; E: sham acupuncture; F: usual care; G: no treatment.

Table 6. Network Meta-Analysis Comparisons of Effectiveness for Reducing Hot Flash Score.

A

-0.02 (-0.23, 0.18) E

-0.15 (-0.34, 0.05) -0.12 (-0.39, 0.14) B

-0.62 (-1.00, -0.24)* -0.59 (-0.91, -0.27)* -0.47 (-0.89, -0.06)* F

*A significant result. A: manual acupuncture; B: electroacupuncture; E: sham acupuncture; F: usual care.

Table 7. Network Meta-Analysis Comparisons of Effectiveness for Improving Menopause-Specific Quality of Life Questionnaire.

C

-0.18 (-0.95, 0.58) E

-0.33 (-1.07, 0.41) -0.15 (-0.35, 0.05) A

-0.46 (-1.38, 0.47) -0.27 (-0.87, 0.32) -0.13 (-0.68, 0.43) B

-0.58 (-1.06, -0.11)* -0.40 (-1.00, 0.20) -0.25 (-0.82, 0.31) -0.13 (-0.92, 0.66) D

-1.31 (-2.44, -0.19)* -1.13 (-1.98, -0.28)* -0.98 (-1.83, -0.13)* -0.86 (-1.87, 0.16) -0.73 (-1.75, 0.29) G

*A significant result. A: manual acupuncture; B: electroacupuncture; C: warm acupuncture; D: hormone replacement therapy; E: sham acupuncture; G: no treatment.

HRT. Acupuncture most frequently caused minor subcutaneous Discussion bleeding. In addition, pain, tingling, heat, swelling, abdominal discomfort, urinary frequency, tiredness, headache, and insomnia Acupuncture therapy is widely used to treat menopausal were also reported. In terms of SA intervention, bleeding, symptoms and other gynecological conditions [1,2]. Developed discomfort, insomnia, irritability, pain, fatigue, and flatulence were from traditional MA, EA and WA are combination therapies: EA reported, whereas nausea, lethargy and breast swelling were caused is where a micro electric current is passed through acupuncture by HRT. However, there were no severe adverse events associated needles and WA adds the thermal stimulation of moxibustion with any intervention. during acupuncture treatment [22,23,38]. ACE is also an integrative therapy that maximizes its therapeutic action with long retention time by implanting absorbable catgut sutures into acupuncture points [39]. Many studies have reported that MA, EA, WA, 120 J Acupunct Res 2021;38(2):110-121

ACE, and even SA are effective at improving HF in menopausal the analysis of HF frequency changes. In addition, few studies women [2,22,23,38,40,41]. The lack of a direct comparison among with small sample size had a greater influence on the estimation different acupuncture treatments makes it difficult to choose of effects. Although there was no significant difference between the clinically best treatment. Thus, the effectiveness of different direct and indirect comparisons, it seemed that the effect size types of acupuncture therapies were compared and ranked using of each intervention was overestimated compared with a direct network meta-analysis according to treatment capacity to reduce comparison. Secondly, most studies included in this review had the frequency and severity of HF, and improve the quality of life of an unclear or high risk of bias in allocation concealment and menopausal women. blinding, which reduced the reliability of the study. In this respect, In this review, 23 RCTs including 2,302 patients suffering when the results of this study were interpreted, the important from menopausal HF were enrolled in a systematic review, and a effect modifiers, such as treatment duration, acupuncture points, network meta-analysis was conducted using 10 of these RCTs. The and severity of symptoms, were considered, and differences in the results of network meta-analysis showed that MA had a higher relative effects between interventions were acceptable. However, probability of reducing HF frequency and severity compared with the estimated effect size was not taken as it was. Finally, it was EA, SA, usual care, or no treatment. Furthermore, WA improved difficult to synthesize the outcome measurements for symptom quality of life of menopausal women significantly more than MA evaluation due to high heterogeneity in the RCTs. In the included or EA. However, studies related to ACE were only included in studies, HFS, visual analog scale, or individual clinical symptom the systematic review due to their high heterogeneity and were scores were used to assess the severity of HF, and the assessment not included in the network meta-analysis. In terms of ranking period also varied from 1 to 7 days. Despite these limitations, this interventions, acupuncture therapy had a higher probability of study would be meaningful as an initial review comparing and reducing HF compared with usual care or no treatment. When ranking the effects of various interventions for menopausal HF. It comparing with HRT, acupuncture was less effective at lowering is highly recommended to seek further evidence through a high the frequency of HF, but was better at increasing quality of life. SA quality RCTs with unified clinical rating scale. had a similar effect or slightly less than MA but had a better effect than EA. Conclusion Comparing the effects of MA and SA, the results for changes in frequency of HF are consistent with previous reviews [1,2,41] but Herein, 23 RCTs were included in the quantitative analysis show a difference in change of HF severity. In previous reviews of which 10 studies were included in network meta-analysis to [1,2,41], MA did not significantly reduce HF frequency, but it compare the effects of various types of acupuncture treatments on significantly reduced the severity of HF when compared with SA. menopausal HF. It was determined that MA was the best option for Notably, in the analysis, only nonpenetrating needles as in SA were alleviating the frequency and severity of HF, and WA for reducing included because of the difference in the effect between shallow MENQOL. There was no statistical difference between MA and needling and nonpenetrating needling [42]. Therefore, there was SA in terms of HF frequency, severity, and MENQOL scores. The little evidence to support differences between the 2 interventions findings of this review should be interpreted with caution due to at reducing HF severity, showing that both interventions were the small number of included studies and the risk of bias in the effective, and MA and SA did not show significantly different original research. efficacy. Previous studies [43,44] have demonstrated that acupuncture Conflicts of Interest therapy, regardless of the type, may alleviate menopausal symptoms by increasing the level of E₂ and decreasing the level of The authors have no conflicts of interests to declare. LH. However, in several studies [18,23] included in this systematic review, serum E₂ and LH levels showed no significant change References comparing before and after treatment. Several studies [45,46] have suggested that estrogen reduction alone is not sufficient to explain [1] Dodin S, Blanchet C, Marc I, Ernst E, Wu T, Vaillancourt C et al. the occurrence of HF. 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