Effect of acupuncture on menopausal hot flushes and serum hormone levels: a systematic review and meta-analysis

Abstract

Objective:

To evaluate the efficacy/effectiveness and safety of acupuncture for the treatment of hot flushes and its impact on serum hormone levels in menopausal women.

Methods:

A total of 10 databases were searched from their inception to August 2018. Reference lists of reviews and included articles were also hand-searched. Randomized controlled trials (RCTs) comparing the effect of acupuncture versus sham acupuncture, or acupuncture versus hormone therapy (HT), as treatment for menopausal hot flushes were included. Outcomes included hot flush frequency, hot flush severity and serum hormone levels of estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Meta-analyses were performed using Review Manager 5.3 software.

Results:

Thirteen RCTs including 1784 patients were selected, seven of which were available for meta-analysis. Compared with sham acupuncture, acupuncture significantly decreased hot flush frequency (mean difference (MD) −0.84, 95% confidence interval (CI) [−1.64, −0.05], I² = 54%) from baseline to the end of study, but did not impact end scores of hot flush frequency (MD 0.19, 95% CI [−0.61, 0.99], I² = 0%) or severity (MD 0.02, 95% CI [−0.13, 0.17], I² = 0%). No differences were found between acupuncture and HT in serum levels of E₂ (MD 6.56, 95% CI [−3.77, 16.89], I² = 76%), FSH (MD 1.06, 95% CI [−1.44, 3.56], I² = 0%) or LH (MD −3.36, 95% CI [−13.37, 6.65], I² = 89%).

Conclusion:

Acupuncture may not decrease hot flush frequency, but yet appears to have similar effects on serum hormone levels as HT, that is, increased E2 and decreased FSH and LH. Considering that no firm conclusions could be drawn due to the low quality and limited number of included trials included, further high-quality RCTs need to be conducted.

Keywords

acupuncture hot flushes menopausal syndromes meta-analysis systematic review

Introduction

Menopause in women typically occurs between the ages of 40 and 58 (average age 52), and symptoms usually lasts 4–5 years or longer; this commonly represents a tough period for women. Over half of menopausal women experience symptoms including hot flushes, night sweats, insomnia, bleeding and sexual dysfunction.¹ Hot flushes are one of the most common vasomotor-related symptoms (VMS), affecting 50%–80% of menopausal women.² Patients frequently suffer from sweating and palpitations without an exact reason. At present, an effective and accepted treatment to manage hot flushes is hormone therapy (HT). However, under certain circumstances, long-term HT may increase risks of coronary events, dementia, venous thromboembolism, breast cancer, gallbladder disease and death from lung cancer.³ Chinese medicine, especially acupuncture, which is an important non-pharmaceutical therapy, has been accepted worldwide for the treatment of many disorders. Acupuncture is one of the non-hormonal interventions that have been reported to be effective for VMS. Several systematic reviews (SRs)^4–6 have examined the efficacy of acupuncture in VMS but have reached conflicting results.

Previous SRs did not always separate hot flushes among breast cancer patients from those attributable to physiologic menopause, which may have led to heterogeneity. For breast cancer patients treated with chemotherapy or patients undergoing oophorectomy, sudden changes in estrogen levels lead to more frequent and severe hot flushes than are typically observed in “normal” menopause.⁷ A recent study showed that hot flushes are due in part, but not entirely, to estrogen depletion at menopause, and symptoms are also related to narrowing of the thermoneutral zone in the heat-regulating center of the hypothalamus.^7,8 Another potential limitation of previous SRs was the inclusion of randomized controlled trials (RCTs) with selective reporting or high risk of bias (RoB) in other domains.

This SR was designed to provide an updated overview, including meta-analysis, of RCTs in this field and further assess the efficacy and safety of acupuncture for hot flushes in menopausal women and its impact on serum hormone levels.

Methods

This review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines.⁹

Literature search strategy

Electronic databases were searched for relevant studies from their inception through 31 August 2018. Seven international databases and three Chinese databases were searched: MEDLINE, Embase, Cochrane Controlled Register of Trials (CENTRAL), EBSCO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP and Wanfang Data. The combination of MeSH terms and keywords included “acupuncture,” “electro-acupuncture,” “hot flushes,” “menopausal” and “menopause syndrome.” We also screened the reference lists of previous SRs related to hot flushes and acupuncture for eligible trials. There were no language restrictions.

Inclusion criteria

RCTs of menopausal syndrome (defined as irregular menstrual cycles or amenorrhea of ⩾2 months with symptoms of hot flushes, sweating or sleep disturbance in women 40–65 years of age) comparing acupuncture with at least one control intervention (i.e. sham acupuncture, HT, normal care or waitlist) were included. RCTs of participants with cancer or a history of radiotherapy/chemotherapy/oophorectomy were excluded. The included trials had to report outcomes in at least one of the following forms: frequency of hot flushes (end score or from baseline to end of study), severity of hot flushes (end score or from baseline to end of study), frequency of hot flushes measured using part of the Kupperman index, menopausal rating scale (MRS) or menopause-specific quality of life (MENQOL) scales, or serum level of estradiol (E2), luteinizing hormone (LH) or follicle-stimulating hormone (FSH). Cluster-randomized trials, crossover studies and academic dissertations were excluded in this study.

Outcome measurements

Primary outcomes were hot flush frequency and severity. Secondary outcomes were serum hormone levels.

Study selection

All articles were screened by two authors (C.L. and T.G.) independently. Any disagreement was solved by group discussion and settled by a third review author (Z.W.). The flow chart of the study selection process is presented in Figure 1.

Data extraction

Data were extracted by two review authors (C.L. and Z.W.) independently. The following information was filled in using a data form: study characteristics (author, year of publication, title, journal, sample size, follow-up), patient characteristics (age range, duration of hot flushes, diagnostic criteria), details of the acupuncture intervention (based on the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) checklist) and comparison groups, outcomes (primary and secondary), withdrawals and adverse events (AEs). Insufficient or missing data were acquired from the author through email by one reviewer (T.G.).

Quality assessment

The Cochrane RoB tool⁹ was used to evaluate the RoB of the included studies by two authors (C.L. and T.G.) independently. Any differences were resolved by the third author (Z.W.).

Data analysis

RevMan 5.3 (Cochrane Collaboration, London, UK), available at www.cochrane.org, was used to perform the statistical analysis. Trials with the same intervention and outcome measurements were grouped together. For continuous data, a weighted mean difference (WMD) and 95% confidence interval (CI) were expressed. Heterogeneity among studies was judged with the Cochrane’s Q and I² statistics. If I² was <50%, a fixed effects model was used; otherwise, a random effects model was used. I² < 50% and p > 0.05 suggested no heterogeneity or low heterogeneity.

Sensitivity analysis

When heterogeneity was significant, low-quality studies were excluded in turns and meta-analyses were repeated. Results were compared and causes of heterogeneity were discussed.

Assessment of reporting bias

We planned to screen for publication bias using a funnel plot if enough primary studies were available.

Results

Search results

A total of 1361 studies were searched initially, 719 of which were excluded as they were duplicates. We went through titles and abstracts of the remaining 642 articles and identified 68 articles for full-text review. Finally, 13 articles^10–22 met the inclusion criteria, 7 of which were suitable for meta-analysis. The characteristics of the included trials are presented in Table 1.

Table 1.

Details of included studies.

Study	Age (mean or range)	Sample size (A/B/C/D)	Intervention		Outcome measures (time points)	Follow-up	Adverse events
Study	Age (mean or range)	Sample size (A/B/C/D)	Experimental	Control	Outcome measures (time points)	Follow-up	Adverse events
Avis et al.¹⁰	53.8	170/39	(A) MA: 20 treatments over 24 weeks	(B) Waitlist control: usual care for 6 months followed by 6-month course of acupuncture treatments	Several time points up to 26 weeks (1) HF frequency (2) HF severity (3) HF daily interference (4) PSQI and PROMIS short form sleep disturbance (5) Women’s health questionnaire (6) Center for Epidemiologic Studies depression scale (7) General anxiety disorder scale and PROMIS short form anxiety (8) Perceived stress scale medical outcomes study short form, physical and mental health component scores	6 weeks	NR
Borud et al.¹¹	45–60	135/133	(A) MA: 10 treatments over 12 weeks + self-care	Self-care alone	(1) HF frequency (baseline to 12 weeks) (2) Health-related QOL measured by the women’s health questionnaire	NR	NR
Ee et al.¹²	55.2	163/164	(A) MA: 10 treatments over 8 weeks	(B) SA (Park sham device): 10 sessions over 8 weeks	8 and 24 weeks: (1) HF frequency (2) HF severity (3) HF score (4) Menopause QOL (5) Hospital anxiety and depression scale (6) Adverse events	12, 24 weeks	NR
Jiang¹³	50.3	65/65	(A) MA + AA: 12 treatments over 12 days	(B) HT: oral nilestriol 2 mg twice a month for 3 months, plus 2 mg medroxyprogesterone in third month three times a day for 7 days	(1) Kupperman index (2) E2, FSH, LH	NR	NR
Kim et al.¹⁴	50.4	27/27	(A) MA: 12 treatments over 4 weeks + UC	(B) Usual care for 4 weeks	(1) Mean reduction in mean 24 h HF score (baseline to week 4) (2) Mean reduction in menopause-related symptoms using the MRS (baseline, 1, 2, 3, 4, 6, 8 weeks)	6, 8 weeks	NR
Kim et al.¹⁵	50.4	27/27	(A) MA: 11 treatments over 7 weeks	(B) SA: 11 treatments over 7 weeks	(1) HF scores: frequency × severity of HF (baseline, 4, 7, 8 weeks) (2) MRS (baseline, 4, 7, 15 weeks)	15 weeks	NR
Liu et al.¹⁶	50.2	80/80	(A) MA + AA: 30 treatments in 39 days	(B) HT: oral tibolone 2.5 mg once a day for 3 months	(1) Modified Kupperman index (2) E2, FSH, LH	NR	NR
Liu et al.¹⁷	48.7	173/174	(A) EA: 24 treatments over 8 weeks	(B) SA: 24 treatments over 8 weeks	(1) MRS HF score (2) MENQOL (4, 8, 20 weeks) (3) FSH, LH, E2, FSH/LH (8, 20 weeks)	24 weeks	NR
Nedeljkovic et al.¹⁸	45–60	10/10/10/10	(A) MA: 12 treatments over 12 weeks	(B) SA: 12 treatments over 12 weeks (C) Chinese herbal medicine, 3 capsules twice daily (D) Placebo, 3 capsules twice daily	Baseline, 12 and 24 weeks (1) HF frequency (2) HF severity (3) MRS II	12 weeks	NR
Painovich et al.¹⁹	57.2	12/9/12	(A) MA: 36 treatments over 3 months	(B) SA: 36 treatments over 3 months (C) Waiting list control: no treatment for 3 months	Baseline, 5 and 12 weeks: (1) Frequency of HF in a 7 day diary (2) Severity of HF in a 7-day diary (3) Severity score (computed as mean severity-weighted no. of VMS per day) (4) MENQOL questionnaire (5) Sleep quality: PSQI (6) Depression: BDI II (7) Anxiety: state-trait (8) Anxiety inventory (9) Hypothalamic-pituitary-adrenal measurements	NR	NR
Venzke et al.²⁰	54.1	27/24	(A) MA: 16 treatments over 12 weeks	(B) SA: 16 treatments over 12 weeks	(1) HF scores using diary (2) Numeric scores on the following scales: Greene climacteric scale, BDI and Beck anxiety scale (at baseline and 4, 13, 24 weeks)	12 weeks	NR
Vincent et al.²¹	45–59	44/44	(A) MA: 10 treatments over 5 weeks	(B) SA: 10 treatments over 5 weeks	Daily HF score (every week)	7 weeks	NR
Wyon et al.²²	48–63	15/13/15	(A) EA: 14 treatments over 12 weeks	(B) SA: 14 treatments over 12 weeks (C) HT: oral 17β-E2 2 mg for 12 weeks	(1) HF frequency (baseline and 4, 8, 12 weeks) (2) Modified Kupperman index (3) General summary of the climacteric symptom intensity scale	6 months	NR

EA: electroacupuncture; AA: auricular acupuncture; MA: manual acupuncture; SA: sham acupuncture; HT: hormone therapy; QOL: quality of life; BDI: Beck Depression Inventory; PSQI: Pittsburgh Sleep Quality Index; E2: estradiol; FSH: follicle-stimulating hormone; LH: luteinzing hormone; MENQOL: menopause-specific quality of life; MRS: menopause rating scale; HF: hot flush; NR: not recorded; PROMIS: Patient-Reported Outcomes Measurement Information System; VMS: vasomotor symptoms.

Study characteristics

All the RCTs were published in journals between 2004 and 2018. One RCT¹⁷ was a multicenter participant-blinded trial, while the rest involved a single center. A total of 1784 participants, aged between 40 and 63, were enrolled in these trials. None of the trials reported calculations of sample size. Nine^{10,12,14,15,17,18,20–22} of them conducted follow-up after treatment. Three trials^18,19,22 compared acupuncture with more than one control group; therefore, they were not included in the meta-analysis.

Interventions

Eight studies compared acupuncture with sham acupuncture.^{12,15,17–22} Three trials compared acupuncture with HT.^13,16,22 The most common course of treatment was 12 weeks,^11,19,20,22 while the remainder ranged from 12 days¹³ to 6 months.¹⁰ For the sham acupuncture intervention, five trials^{15,17,18,21,22} inserted needles parallel 1–5 cm away from the traditional acupuncture point locations that were targeted for electroacupuncture (EA) without use of additional stimulation; three trials^12,19,20 avoided penetrating the skin (using small plastic rings), among which one²⁰ used sham electrical stimulation (four needles were connected to a disabled acupuncture device). All trials used standard traditional acupuncture point locations for acupuncture, while two of them^13,16 used body acupuncture combined with auricular acupuncture (AA). Two trials^17,22 used EA, while the remaining 11 trials used manual acupuncture (MA). The depth of needle insertion ranged from 0.2 mm to 30 cm. All trials except for one required manual simulation to achieve de qi needling sensation.¹³

Risk of bias

One trial²² used an inadequate randomization procedure of selecting odd or paired numbers, and so was judged to be at high risk of selection bias. The rest of the trials described adequate methods of random sequence generation using a randomization table and thus were rated as low risk for selection bias in terms of random sequence generation. Seven trials^{10,11,12,15,17,18,20} mentioned using an opaque envelope for allocation concealment, while five trials^{13,14,16,19,21} were rated as having unclear risk of selection bias of allocation concealment, since they did not give detailed information about the process of random number generation. Five trials^{12,15,17,18,20} used sham acupuncture in the control group, so for risk of performance bias, they were rated as being at low risk; others were high risk as all were open label trials without SA and so blinding of participants was impossible by design. For detection bias, all included trials were rated as being high risk because it was similarly not possible to blind acupuncturists by design. The remaining eight trials^{10,11,13,14,16,19,21,22} were also rated as being at high risk of performance bias because the treatments for participants were usual care, oral HT or waitlist. Only one trial¹⁵ mentioned blinding of the outcome assessment, while the others did not, so only this one trial was rated as being at low risk of detection bias and the remaining were deemed to be of unclear risk. All trials reported all expected outcomes and data, so they were evaluated as low risk for attribution bias. However, two of them^10,18 failed to report detailed information on reasons for drop-outs, so they were judged to have an unclear risk of reporting bias. Other sources of bias were deemed to be low risk for all trials because baseline information, findings, ethical approval and other details were all fully reported. A summary of the overall RoB assessment is presented in Figure 2. Details of the RoB assessment is presented in Figure 3.

Efficacy/effectiveness of acupuncture

Acupuncture versus sham acupuncture

Three^12,20,21 studies with 466 participants reported hot flush frequency as end scores. There were no significant differences between groups (WMD 0.19, 95% CI [−0.61, 0.99], I² = 0%, p = 0.64; Figure 4). Two studies^15,17 with 401 participants reported differences in hot flush frequency from baseline to the end of the study. The pooled data indicated that acupuncture significantly decreased hot flush frequency compared with sham acupuncture (WMD -0.84, 95% CI [−1.64, −0.05], I2 = 54%, p = 0.04).

Two studies^15,17 with 415 participants reported hot flush severity as end scores. There was a significant difference between groups (WMD −0.02, 95% CI [−0.13, −0.17], I2 = 0%, p = 0.79, n = 415).

Three trials^18,19,22 comparing hot flush frequency following acupuncture versus sham acupuncture were excluded from the meta-analysis since they compared the effect of acupuncture with more than one control group. One trial²² including 43 participants suggested that EA decreased hot flush frequency significantly over time, but not to the same extent as estrogen treatment. No significant difference in effect was found between EA and superficial needle insertion. One trial¹⁹ with 33 participants reported exit-entry values of VMS frequency and severity, and suggested that both the acupuncture and sham acupuncture groups demonstrated improved VMS trends compared with the waiting list control group (Δ −3.5 ± 3.00 vs −4.1 ± 3.79 vs −1.2 ± 2.4, respectively). One trial¹⁸ with 20 participants suggested acupuncture induced a significant decline in hot flush frequency (p = 0.016) and severity (p = 0.013) pre- versus post-treatment compared with sham acupuncture. Another trial¹⁵ including 54 participants comparing hot flush severity following acupuncture versus sham acupuncture found the mean change in hot flush scores was −6.4 ± 5.2 in the verum acupuncture group and −5.6 ± 9.2 in the sham group (10.0 ± 8.1 vs 11.7 ± 12.6, respectively; p = 0.081).

Acupuncture versus HT

Only one trial¹³ reported whole Kupperman index scores, and the authors did not provide original data on hot flush frequency. One trial²² reported a significant decrease in hot flush score between the acupuncture group and HT group (3.12 ± 0.98 vs 4.09 ± 1.28, p < 0.05).

Two trials with 290 participants compared the effects of acupuncture and HT on serum hormone levels. There were no statistically significant differences in serum levels of E2 (WMD −6.56, 95% CI [−3.77, 16.89], I2 = 76%, p = 0.21), FSH (WMD 1.06, 95% CI [−1.44, 3.56], I2 = 0%, p = 0.41) or LH (WMD −3.36, 95% CI [−13.37, 6.65], I2 = 89%, p = 0.51) between HT and acupuncture.

Acupuncture versus usual care or waitlist

One trial¹⁴ compared hot flush scores between acupuncture and usual care and found a difference in score of 9.64 (p < 0.001). A second trial¹¹ suggested acupuncture decreased hot flush frequency more than self-care with a difference in score of 2.1 (p < 0.001) and also decreased hot flush severity with a difference in score of 1.4 (p < 0.001). A third trial¹⁰ used a waitlist control group and suggested that VMS frequency declined by 36.7% at 6 months in the acupuncture group and increased by 6.0% in the control group (p < 0.001).

Safety

One of the RCTs¹⁶ reported a 5% AE rate in the acupuncture group, which was significantly lower than the 19% reported in the HT group (χ2 = 7.227, p < 0.05). None of the other trials mentioned AEs.

Discussion

Principal findings

This SR reviewed RCTs of acupuncture to assess the efficacy/effectiveness and safety of this therapy for the treatment of hot flushes in menopausal syndrome. Unlike previous SRs, this review was conducted using strict inclusion criteria, which deliberately excluded the management of hot flushes caused by artificial interventions, for example, chemotherapy after cancer. This review considered changes in serum hormone levels, which are typical in menopausal syndromes and, to our knowledge, not been included by previous SRs. Our pooled results indicated that acupuncture decreased the frequency of hot flushes (from baseline to the end of the included studies) and did not differ from HT in terms of its impact on serum hormone levels. However, our meta-analysis of end scores for hot flush frequency/severity provided conflicting results. Although inclusion of the trials was subject to stricter criteria than previous SRs, this positive result should be interpreted cautiously, since heterogeneity was high. Possible sources of heterogeneity include limited numbers of participants and unclear selection bias.

Possible explanations

Previous experiments have suggested that acupuncture can impact VMS by modulating the hypothalamic-pituitary-ovarian (HPO) axis and/or neurotransmitters. Acupuncture has also been shown to increase E2 levels and decrease FSH and LH in menopausal rats.²³ Low frequency acupuncture can also decrease the expression of calcitonin gene-related peptide (CGRP) and may thereby improve hot flushes.²⁴ The results of our meta-analysis are in accordance with this fundamental research.

Implications

To our knowledge, none of the trials estimated the required sample size before they were conducted, and sample sizes varied from 12 to 173. In future research, it is important to calculate sample size to ensure that RCTs are adequately powered. Sham acupuncture was conducted differently between the included trials. Controversy exists regarding the necessity of and optimal methodology for conducting sham acupuncture. According to Cochrane’s tool for the assessment of RoB, only if outcomes were entirely objective, for example, hormone level or pregnancy rate, can a study without sham acupuncture be rated as having a low risk of bias. However, trials²⁵ have suggested that sham acupuncture may also be effective, which potentially renders it improper as a control intervention. Therefore, HT may represent a better control intervention when probing the effect of acupuncture on menopausal syndromes.

Limitations

There were some limitations to this study. First, few studies reported the evaluation of hot flushes and hormone levels at the same time. Due to limitations on the number of participants, it would be not be proper to draw a conclusion regarding the effect of acupuncture on serum hormone levels in menopausal hot flushes. Applications of this review were limited since the number of included trials was small. Second, the age range of the participants in the included trials varied (45–60), which introduced a high degree of clinical heterogeneity that may have impacted the results of the analysis. High heterogeneity could also have been due to other variations in the physical condition of the patients recruited, including body weight, race, marital status, educational level, dietary habit and other conditions.

Conclusion

This review indicated that acupuncture may not decrease hot flush frequency, but yet appears to have similar effects on serum hormone levels as HT, that is, increased E2 and decreased FSH and LH. Given the limited number of participants and heterogeneity among the included studies, we were unable to draw any strong conclusions regarding the efficacy/effectiveness and safety of acupuncture for menopausal hot flushes.

Footnotes

Acknowledgements

The authors thank Shuyuan Lin, who is funded by the Youth Research and Innovation Foundation of Zhejiang Chinese Medical University.

Contributors

CL and ZW contributed equally to this work. CL and ZW conceived the study, designed the study protocol and drafted the manuscript. CL and TG were responsible for study selection. CL and ZW worked together to extract data from articles. TG and CL evaluated study quality. XG and LZ gave advice for writing and revising this manuscript, and XG provided financial support. All authors contributed to the editing of the manuscript, and read and approved the final version accepted for publication.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Efficacy Evaluation Model Study of Taiyin Disease Base on CNN provided financial support for this systematic review.

Patient consent

This is a systematic review which does not contain any personal medical information about an identifiable person, so patient consent is not applicable.

ORCID iD

Chang Liu

References

Mangione

Briceland Betts

Elleberg

, et al. NIH state of the science conference statement on management of menopause-related symptoms. NIH Consens State Sci Statements 2005; 22(1): 1–38.

Abdi

Mobedi

Roozbeh

. Hops for menopausal vasomotor symptoms: mechanisms of action. J Menopausal Med 2016; 22(2): 62–64.

Van Leer

. The risk of cardiovascular disease, fracture, dementia, and cancer after long-term hormone therapy in perimenopausal and postmenopausal women. Am Fam Physician 2018; 98: 117–118.

Dodin

Blanchet

Marc

, et al. Acupuncture for menopausal hot flushes. Cochrane Database Syst Rev 2013; 7: CD007410.

French

Xue

, et al. Acupuncture for menopausal hot flashes: clinical evidence update and its relevance to decision making. Menopause 2017; 24(8): 980–987.

Befus

Coeytaux

Goldstein

, et al. Management of menopause symptoms with acupuncture: an umbrella systematic review and meta-analysis. J Altern Complement Med 2018; 24(4): 314–323.

Carpenter

Elam

Ridner

, et al. Sleep, fatigue, and depressive symptoms in breast cancer survivors and matched healthy women experiencing hot flashes. Oncol Nurs Forum 2004; 31(3): 591–5598.

Freedman

. Hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol 2014; 142: 115–120.

Liberati

Altman

Tetzlaff

, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: W65–W94.

10.

Avis

Coeytaux

Isom

, et al. Acupuncture in menopause (AIM) study—a pragmatic, randomized controlled trial. Menopause 2016; 23(6): 626–637.

11.

Borud

Alraek

White

, et al. The Acupuncture on hot flushes among menopausal women (ACUFLASH) study, a randomized controlled trial. Menopause 2009; 16(3): 484–493.

12.

Xue

Chondros

, et al. Acupuncture for menopausal hot flushes: a randomised sham-controlled trial. Adv Integr Med 2016; 2: 115–116.

13.

Jiang

. Clinical observation of abdominal acupuncture plus auricular point pressure for perimenopausal syndrome. Shandong Journal of Traditional Chinese Medicine 2011; 30: 31–33.

14.

Kim

Kang

Kim

, et al. Effects of acupuncture on hot flashes in perimenopausal and postmenopausal women—a multicenter randomized clinical trial. Menopause 2010; 17(2): 269–280.

15.

Kim

Jeong

Kim

, et al. Acupuncture for hot flushes in perimenopausal and postmenopausal women: a randomised, sham-controlled trial Acupunct Med 2011; 29(4): 249–256.

16.

Liu

. Syndrome differentiation acupuncture combined with auricular acupressure for treating perimenopausal syndrome. Global Chin Med 2017; 10: 744–747.

17.

Liu

Wang

, et al. Acupuncture for symptoms in menopause transition: a randomized controlled trial. Am J Obstet Gynecol 2018; 219(4): 373.e1–373.e10.

18.

Nedeljkovic

Tian

. Effects of acupuncture and Chinese herbal medicine (Zhi Mu 14) on hot flushes and quality of life in postmenopausal women: results of a four-arm randomized controlled pilot trial. Menopause 2014; 21: 15–24.

19.

Painovich

Shufelt

Azziz

, et al. A pilot randomized, single-blind, placebo-controlled trial of traditional acupuncture for vasomotor symptoms and mechanistic pathways of menopause. Menopause 2012; 19(1): 54–61.

20.

Venzke

Calvert

Jr Gilbertson

, et al. A randomized trial of acupuncture for vasomotor symptoms in post-menopausal women. Complement Ther Med 2010; 18(2): 59–66.

21.

Vincent

Barton

Mandrekar

, et al. Acupuncture for hot flashes—a randomized, sham-controlled clinical study. Menopause 2007; 14(1): 45–52.

22.

Wyon

Wijma

Nedstrand

, et al. A comparison of acupuncture and oral estradiol treatment of vasomotor symptoms in postmenopausal women. Climacteric 2004; 7(2): 153–164.

23.

Zhao

Tian

Cheng

, et al. Electroacupuncture enhances extragonadal aromatization in ovariectomized tats. Reprod Biol Endocrinol 2004; 27: 18.

24.

Wei

Shou

, et al. Effects of electroacupuncture at 2 and 100 Hz on rat type 2 diabetic neuropathic pain and hyperalgesia-related protein expression in the dorsal root ganglion. J Zhejiang Univ Sci B 2017; 18(3): 239–248.

25.

Manheimer

. Selecting a control for in vitro fertilization and acupuncture randomized controlled trials (RCTs): how sham controls may unnecessarily complicate the RCT evidence base. Fertil Steril 2011; 95: 2456–2461.