Original Research ajog.

org

GYNECOLOGY
Acupuncture for symptoms in menopause transition:
a randomized controlled trial
Zhishun Liu, MD, PhD; Yanke Ai, MD, PhD; Weiming Wang, MD, PhD; Kehua Zhou, MD, DPT; Liyun He, MD, PhD;
Guirong Dong, MD, PhD; Jianqiao Fang, MD, PhD; Wenbing Fu, MD, PhD; Tongsheng Su, MD; Jie Wang, MD, PhD;
Rui Wang, MD; Jun Yang, MD; Zenghui Yue, MD; Zhiwei Zang, MD; Wei Zhang, MD, PhD; Zhongyu Zhou, MD;
Huanfang Xu, MD, PhD; Yang Wang, MD, PhD; Yan Liu, MD; Jing Zhou, MD; Likun Yang, MD; Shiyan Yan, PhD;
Jiani Wu, MD, PhD; Jia Liu, MD, PhD; Baoyan Liu, MD

BACKGROUND: Acupuncture has been used for women during
menopause transition, but evidence is limited.
OBJECTIVE: We sought to evaluate the efficacy of electroacupuncture
on relieving symptoms of women during menopause transition.
STUDY DESIGN: We conducted a prospective, multicenter, random-
ized, participant-blinded trial in China mainland. Subjects were randomized
to receive 24 treatment sessions of electroacupuncture at traditional acu-
points or sham electroacupuncture at nonacupoints over 8 weeks with 24
weeks’ follow-up. Primary outcome was the change from baseline in the
total score of Menopause Rating Scale at week 8. Secondary outcomes
included the changes from baseline in the average 24-hour hot flash score,
the Menopause Rating Scale subscale scores, the total score of Menopause-
Specific Quality of Life Questionnaire and its subscales, and serum female
hormones. All analyses were performed with a 2-sided P value of < .05
considered significant based on the intention-to-treat principle.
RESULTS: A total of 360 women (180 in each group) with menopause-
related symptoms during menopause transition were enrolled from June 9,
2013, through Dec 28, 2015. At week 8, the reduction from baseline in the
Menopause Rating Scale total score was 6.3 (95% confidence interval,
5.0e7.7) in the electroacupuncture group and 4.5 (95% confidence
interval, 3.2e5.8) in the sham electroacupuncture group with a
between-group difference of 1.8 (95% confidence interval, 0.9e2.8; P ¼
.0002), less than the minimal clinically important difference of 5 points’
reduction. For secondary outcomes, the between-group differences for the
decrease in the mean 24-hour hot flash score were significant at weeks 8,
20, and 32, but all were less than the minimal clinically important dif-
ference in previous reports. Interestingly, the between-group differences
for the Menopause-Specific Quality of Life Questionnaire total score
reduction were 5.7 at week 8, 7.1 at week 20, and 8.4 at week 32, greater
than the minimal clinically important difference of 4 points. Changes from
baseline in follicle-stimulating hormone, luteinizing hormone, and estradiol
levels at weeks 8 and 20 (P > .05 for all), with the exception of follicle-
stimulating hormone/luteinizing hormone ratios (P ¼ .0024 at week 8
and .0499 at week 20), did not differ between groups.
CONCLUSION: Among women during menopause transition, 8 weeks’
electroacupuncture treatment did not seem to relieve menopausal
symptoms, even though it appeared to improve their quality of life.
Generalizability of the trial results may be limited by mild baseline
menopausal symptoms in the included participants.
Key words: acupuncture, hot flash, menopause transition, Menopause
Rating Scale, Menopause-Specific Quality of Life

Introduction
Menopause transition (MT) is the tran-
sitional period between reproductive
stage and menopause in women; it is
marked by increased variability in men-
strual cycle length, fluctuations in hor-
monal levels, and increased prevalence of
anovulation.1 On average, MT starts
when women are in their mid-to-late
40s, and lasts for 5e8 years.2 Clinical
symptoms of MT usually include hot
Cite this article as: Liu Z, Ai Y, Wang W, et al.
Acupuncture for symptoms in menopause transition: a
randomized controlled trial. Am J Obstet Gynecol
2018;219:373.e1-10.
0002-9378/$36.00
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.08.019
flash (HF), fatigue, sleep disturbances,
anxiety, irritability, weight gain, vaginal
dryness, and urinary incontinence.3,4
Hormone replacement therapy is the
most effective treatment for the relief of
vasomotor symptoms, usually described
as night sweats, HF, and flashes, in
menopause.5 Unfortunately, because of
side effects, the use of hormone
replacement therapy has been highly
controversial and is not explicitly rec-
ommended for women who enter MT.5
Women and their physicians some-
times choose acupuncture for perimen-
opausal symptoms.6,7 Based on previous
studies, a consensus has emerged that
acupuncture is safe and more effective
for menopausal symptoms than no
treatment, but not better than sham
acupuncture.8e11 However, these results
may not be generalizable across women
during MT as the available studies
mainly focused on acupuncture treat-
ment for postmenopausal women.8e12
The objective of this study was to
investigate the efficacy of electro-
acupuncture (EA) vs sham EA (SA) for
menopausal symptoms during MT.
Materials and Methods
Design overview
We conducted a prospective, multicenter,
randomized, participant-blinded trial at
12 hospitals in China mainland (Beijing;
Shanghai; Hangzhou, Zhejiang; Guangz-
hou, Guangdong; Xi’an, Shaanxi; Taiyuan,
Shanxi; Jinan, Shandong; Hefei, Anhui;
Hengyang, Hunan; Yantai, Shandong;
Changsha, Hunan; and Wuhan, Hubei).
The trial protocol13 was approved by the
ethics committee from each of the 12 sites
(ClinicalTrial.gov, no. NCT01849172).

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Participants were recruited by advertise-

AJOG at a Glance ments. All participants signed informed
Why was this study conducted? consent and were preliminarily screened
To evaluate the efficacy of electroacupuncture on relieving symptoms of women by research assistants. Diagnosis was made
during menopause transition. by gynecologists at each site.

Key findings Participants

The reductions of Menopause Rating Scale total scores at weeks 8, 20, and 32 To be included in the trial, women ful-
supported statistical but not clinical meaningful differences between electro- filled all the following criteria: (1) vari-
acupuncture and sham electroacupuncture on the improvement of menopausal ability in menstrual cycle length with a
symptoms. persistent difference of 7 days in the
past 12 months (early MT) or the
What does this add to what is known? occurrence of amenorrhea of 2 months
This trial does not support electroacupuncture in relieving menopausal symp- but no more than 12 months (late MT);1
toms in women during menopause transition, even though electroacupuncture (2) MT symptoms such as HF, sweating,
might improve quality of life in these women. sleep disturbance, migraine, anxiety,
vaginal dryness, and sexual problems;
and (3) age between 40e55 years.
Main exclusion criteria include: (1)
received estrogen, serotonin-reuptake
FIGURE inhibitors, or other alternative therapies
Flow of participants through trial 4 weeks prior to enrollment; (2) cryp-
togenic vaginal bleeding, ovarian cyst,
tumor, oophorectomy, or hysterectomy;
(3) history of radiotherapy or chemo-
therapy, anticoagulant use, or regular use
of sedatives or anxiolytics; and (4)
pregnant or plan to become pregnant or
breast-feeding (Appendix 1, 2.4.2.2
Exclusive Criteria).

Randomization and masking

We randomly assigned each participant to
EA or SA groups via a central randomi-
zation system using a 1:1 ratio. Random-
ization was stratified by site with a fixed
block size of 6. Except acupuncturists,
all relevant parties were blinded to group
assignment. Participants of different
groups were treated separately. To
examine the effect of blinding, researchers
asked participants to guess whether they
received EA or SA at weeks 4 and 8.

Interventions
The acupuncture regimen was based on
literature review and consensus of
acupuncture experts. Acupuncturists all
had completed an undergraduate edu-
cation or higher in acupuncture and had
at least 2e3 years’ experience. All re-
searchers received 1 day of training prior
to participant enrollment. Participants
received 24 sessions of EA or SA, 30
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018. minutes each session, over 8 weeks (3
times per week), and were followed up

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for 24 weeks. During study, we discour-

TABLE 1
aged participants from receiving any
Baseline characteristics of randomized participants
other treatment for menopause symp-
toms and asked them to make appro- Sham
priate documentation if they received Electroacupuncture electroacupuncture
such treatment. Characteristics n ¼ 180 n ¼ 180
Participants in the EA group received Age, y, mean  SDa 48.7  4.0 48.1  3.8
EA at RN4, bilateral ST25, bilateral EX- Race, n (%)
CA1, and bilateral SP6.14 We used Hua-
Han 177 (98.3) 176 (97.8)
tuo disposable needles and EA apparatus
(SDZ-V; Suzhou Medical Appliance, Other 3 (1.7) 4 (2.2)
Jiangsu, China). With participants supine Marital status, n (%)
and sterile stick adhesive pads placed, Married 180 (100.0) 179 (99.4)
acupuncturists inserted 0.35-  75-mm
Not married 0 (0.0) 1 (0.6)
needles vertically through the pads into
ST25, EX-CA1, and RN4 for approxi- BMI, kg/m , mean  SD
2
22.9  2.3 22.9  2.6
mately 30e70 mm until they pierced into Menopausal stage, n (%)
the muscle layer of the abdominal wall; Early MT 81 (45.0) 96 (53.3)
acupuncturists inserted 0.35-  40-mm
Later MT 99 (55.0) 84 (46.7)
needles vertically at bilateral SP6
through the pads for approximately 20 Duration of MT, y, mean  SD 1.4  1.2 1.3  1.3
mm. Acupuncturists performed gentle Comorbidities, n (%)
needle manipulations at RN4 and SP6
Hypertension 2 (1.1) 4 (2.2)
with 3 (once every 10 minutes) small
equal lifting, thrusting, and twisting ma- Thyroid diseases 1 (0.6) 3 (1.7)
nipulations to reach de qi, which was Diabetes 0 (0.0) 1 (0.6)
described as soreness, heaviness, and Gynecological diseases 1 (0.6) 1 (0.6)
distension sensation.15 Research assis- Allergic disease 1 (0.6) 2 (1.1)
tants attached paired alligator clips from
the EA apparatus transversely to the Others 10 (5.6) 6 (3.3)
needle holders at bilateral ST25 and EX- Patients using other measures during screen stage, n (%)
CA1. EA stimulation lasted for 30 mi- Acupuncture 1 (0.6) 0 (0.0)
nutes with a dilatational wave of 10/50 Hz
Chinese herbal medicines 4 (2.2) 2 (1.1)
and current intensity of 0.1e1 mA
depending on participant’s comfort level Antidiabetic drugs 0 (0.0) 1 (0.6)
(preferably with skin around the acu- Drugs for thyroid diseases 1 (0.6) 1 (0.6)
points shivering mildly without pain). MRS total score, mean  SD 17.0  6.5 16.7  6.7
Participants in the SA group received
Somatic-vegetative domain 6.7  2.8 6.6  2.8
needling at nonacupoints laterally and
horizontally 1e2 cun (approximaly 1-2 Psychological domain 6.7  3.0 6.6  3.3
inches) off the corresponding acupoints. Urogenital domain 3.6  2.3 3.5  2.5
Procedures, electrode attachments, and 24-h HF score, mean  SD 7.1  7.9 5.9  5.6
other treatment settings were the same as
MENQOL total score, mean  SD 61.3  28.6 60.2  28.3
in the EA group, but 0.30-  25-mm
blunt needles and specially constructed Vasomotor domain 7.6  4.3 7.4  4.0
EA apparatus were used with no skin Psychosocial domain 15.3  8.4 14.7  8.1
penetration, electricity output, or de qi Physical domain 33.3  16.8 33.5  17.4
requirement (Appendix 1, 4.2) (SA).
Sexual functioning domain 5.1  4.3 4.7  4.4

Outcomes Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018. (continued)

The primary outcome was the change

from baseline in the Menopause Rating
Scale (MRS) (range, 0 [best] to 44 [worst]
outcomes, 5 as minimal clinically impor-
tant difference [MCID])16,17 total score at
week 8. A prespecified subgroup (early
and late MT) analysis was performed for
the primary outcome. We chose MRS,
rather than 24-hour HF score, as the pri-
mary outcome, because menopausal
symptoms vary by race and the prevalence
of HF or night sweats in Chinese women
does not differ from that of other indi-
vidual menopausal symptoms.18,19 MRS
thus is more likely to capture the global
impact of menopausal symptoms on

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FSH, LH, E2, and FSH/LH between

TABLE 1
Baseline characteristics of randomized participants (continued)
Sham
Electroacupuncture electroacupuncture
Characteristics n ¼ 180 n ¼ 180
Serum female hormones, mean  SDb
FSH, mIU/mL 44.7  31.8 43.6  31.3
E2, pmol/L 182.8  279.2 196.5  304.1
LH, mIU/mL 25.3  17.7 25.8  18.2
FSH/LH 2.0  0.9 1.8  0.8
BMI, body mass index; E2, estradiol; FSH, follicle-stimulating hormone; HF, hot flash; LH, luteinizing hormone; MENQOL,
Menopause-Specific Quality of Life Questionnaire; MRS, Menopause Rating Scale; MT, menopause transition.
a
Two participants in electroacupuncture group, aged 39 and 59 y, were included by mistake; b One participant in electro-
acupuncture group and 1 participant in sham acupuncture group had missing data for FSH, LH, and FSH/LHeadditionally, 27
patients in electroacupuncture group and 19 patients in sham electroacupuncture group had missing data for E2.
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018.
participants and their response to week 8 would be the same for EA and SA,
acupuncture in Chinese women. and otherwise as the alternative hy-
Secondary outcomes included the pothesis. Our unpublished pilot study
following: the change from baseline in showed that the change in the SD of MRS
the MRS total score at weeks 4, 20, and total score from baseline at week 8 was
32; the change in the MRS subscale 9.96 in the EA group and 7.39 in the SA
(somatic-vegetative, psychological, and group, and the pooled variance of the 2
urogenital domains; not prespecified) groups was 96.7. Considering the varia-
scores at weeks 4, 8, 20, and 32; the tion of multicenter research, we multi-
change from baseline in the average 24- plied the pooled variance by 1.5 times to
hour HF score (the sum of [daily HF 115.3 and calculated the required sample
episodes multiplied by the correspond- size to detect a between-group difference
ing severities {mild ¼ 1, moderate ¼ 2, of 517 with 95% power and 5% of the
severe ¼ 3}]/7) at weeks 4, 8, 20, and significance level using PROC POWER
32;20,21 the change from baseline in the in SAS (SAS Institute Inc, Cary, NC),
total and subscale scores of Menopause- which resulted in 120 cases for each
Specific Quality of Life Questionnaire group. For an estimated 20% dropout
(MENQOL) (0 [best] to 174 [worst] rate using the sophisticated mixed effects
outcomes, 4 as MCID) at weeks 4, 8, 20, model, 180 participants were planned in
and 32;22,23 and the change from base- each group.
line in serum female hormones (follicle- All analyses were based on the
stimulating hormone [FSH], luteinizing intention-to-treat principle. We
hormone [LH], and estradiol [E2], and analyzed the change in the MRS total
the ratio of FSH/LH) at weeks 8 and 20. score from baseline at week 8 by fitting a
Serum reproductive hormones were mixed effect model using baseline value
measured during weeks 8 and 20, be- as a covariate, treatment as a fixed effect,
tween days 2e4 of menstruation or at and site as a random effect. We con-
random if amenorrhea. ducted the prespecified subgroup anal-
Adverse events (AEs) were recorded ysis by adding the interaction between
throughout the trial and were catego- menopausal stage (early and late MT)
rized by the acupuncturists and clinical and group into the mixed effect model.
specialists into treatment-related or We used the same approach for sec-
nontreatment-related AEs. ondary outcomes of the MRS total and
subscale scores, the 24-hour HF score,
Statistical analysis and the MENQOL total and subscale
The null hypothesis was that the change scores. We used independent t test or
from baseline in the MRS total score at Wilcoxon rank sum test to compare
groups. The c2 test or Fisher exact test
was used for other (categorical)
outcomes.
We used the multiple imputation
method for incomplete data on the pri-
mary outcome under missing at random
assumption (Appendix 2, eTable 1), and
then conducted 2 post hoc sensitivity an-
alyses using a control-based pattern-
mixture model and a worst-case analysis
for the primary outcome data
(Appendix 2, eTables 2 and 3). Secondary
outcomes were performed in the observed
cases without imputation of missing data.
All analyses were performed with
software (SAS, Version 9.4) with a
2-sided P value of <.05 considered sig-
nificant. No interim analysis was un-
dertaken. Subgroup analyses and post
hoc sensitivity analyses were not
adjusted for multiple comparisons, and
their results should be interpreted as
exploratory.
Results
From June 9, 2013, through Dec 28,
2015, we screened 743 participants and
randomly assigned 360 participants to
EA (n ¼ 180) or SA (n ¼ 180) group.
Among the randomized participants, 13
(3.6%) dropped out during study: 7
(3.8%) in the EA group and 6 (3.3%) in
the SA group (Figure). Baseline charac-
teristics of the participants were similar
between groups (Table 1).
Participants received 23.2 sessions of
treatment in the EA group and 23.3
sessions in the SA group; 96.7% partic-
ipants in the EA group and 97.2% in the
SA group received at least 20 (80%) of
the planned treatment sessions. One
participant in EA group and 2 partici-
pants in SA group did not receive any
treatment.
For primary endpoint, data in 6
(3.3%) participants in the EA group and
5 (2.7%) participants in the SA group
were imputed. The MRS total score was
17.0 (95% confidence interval [CI],
16.0e17.9) at baseline and 10.5 (95% CI,
9.7e11.4) at week 8 in the EA group, and
16.7 (95% CI, 15.7e17.7) at baseline and
12.2 (95% CI, 11.2e13.2) at week 8 in
the SA group. The reduction from
baseline in the mean of the MRS total

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TABLE 2
Primary and secondary outcomesa

Electroacupuncture Sham electroacupuncture Between-group difference

Outcomes n ¼ 180 n ¼ 180 Value P value
Primary outcome
MRS total score at wk 8, mean (95% CI) 10.5 (9.7e11.4) 12.2 (11.2e13.2)
Change from baseline in MRS total 6.3 (5.0e7.7) 4.5 (3.2e5.8) 1.8 (0.9e2.8) .0002
score at wk 8, adjusted mean (95% CI)b,c
Secondary outcomesd
Change from baseline in MRS total score,
adjusted mean (95% CI)c
Wk 4 3.6 (2.6e4.6) 3.2 (2.2e4.2) 0.4 (e0.4 to 1.3) .3073
Wk 20 7.0 (5.5e8.4) 4.5 (3.1e5.9) 2.5 (1.5e3.4) <.0001
Wk 32 6.8 (5.2e8.5) 4.1 (2.5e5.8) 2.7 (1.7e3.6) <.0001
Change from baseline in somatic-vegetative
domain of MRS, adjusted mean (95% CI)c
Wk 4 1.5 (1.1e2.0) 1.4 (1.0e1.8) 0.2 (e0.2 to 0.5) .4048
Wk 8 2.6 (2.0e3.2) 1.9 (1.4e2.5) 0.7 (0.3e1.1) .0015
Wk 20 3.0 (2.4e3.5) 2.0 (1.5e2.5) 1.0 (0.6e1.4) <.0001
Wk 32 2.8 (2.2e3.4) 1.7 (1.2e2.3) 1.0 (0.6e1.5) <.0001
Change from baseline in psychological
domain of MRS, adjusted mean (95% CI)c
Wk 4 1.6 (1.1e2.1) 1.5 (1.0e2.0) 0.1 (e0.3 to 0.5) .5690
Wk 8 2.7 (2.1e3.3) 2.0 (1.4e2.6) 0.7 (0.2e1.1) .0045
Wk 20 2.9 (2.2e3.6) 2.0 (1.3e2.7) 0.9 (0.4e1.3) .0004
Wk 32 3.0 (2.2e3.7) 2.0 (1.3e2.8) 1.0 (0.5e1.4) <.0001
Change from baseline in urogenital
domain of MRS, adjusted mean (95% CI)c
Wk 4 0.5 (0.2e0.7) 0.3 (0.1e0.6) 0.2 (e0.2 to 0.5) .3668
Wk 8 1.0 (0.7e1.4) 0.5 (0.2e0.8) 0.5 (0.2e0.9) .0011
Wk 20 1.1 (0.7e1.5) 0.5 (0.1e0.9) 0.6 (0.3e1.0) .0007
Wk 32 1.0 (0.6e1.5) 0.4 (e0.1 to 0.9) 0.7 (0.3e1) .0006
Change from baseline in mean 24-h HF
score, adjusted mean (95% CI)c
Wk 4 1.9 (1.0e2.8) 1.9 (0.9e2.8) 0.0 (e0.6 to 0.7) .9013
Wk 8 3.6 (2.6e4.7) 2.5 (1.4e3.5) 1.2 (0.6e1.8) .0001
Wk 20 3.9 (2.9e4.8) 2.7 (1.7e3.7) 1.1 (0.6e1.7) <.0001
Wk 32 4.1 (2.7e5.5) 1.9 (0.5e3.2) 2.2 (1.1e3.3) <.0001
Change from baseline in MENQOL
total score, adjusted mean (95% CI)c
Wk 4 12.8 (8.6e17.0) 12.6 (8.4e16.8) 0.2 (e3.2 to 3.5) .9267
Wk 8 22.8 (16.9e28.7) 17.1 (11.2e23.0) 5.7 (1.9e9.5) .0033
Wk 20 25.3 (18.9e31.7) 18.2 (11.9e24.6) 7.1 (3.4e10.7) .0002
Wk 32 26.0 (19.4e32.7) 17.6 (11.0e24.3) 8.4 (4.8e12.0) <.0001
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TABLE 2
Primary and secondary outcomesa (continued)

Electroacupuncture Sham electroacupuncture Between-group difference

Outcomes n ¼ 180 n ¼ 180 Value P value
Change from baseline in vasomotor
domain of MENQOL, adjusted mean (95% CI)c
Wk 4 1.9 (1.1e2.8) 1.7 (0.9e2.6) 0.2 (e0.3 to 0.7) .4707
Wk 8 3.4 (2.4e4.4) 2.5 (1.5e3.5) 0.9 (0.4e1.5) .0009
Wk 20 3.7 (2.7e4.7) 2.7 (1.6e3.7) 1.1 (0.5e1.6) .0003
Wk 32 3.8 (2.8e4.8) 2.4 (1.4e3.4) 1.4 (0.8e2.0) <.0001
Change from baseline in psychosocial
domain of MENQOL, adjusted mean (95% CI)c
Wk 4 2.8 (1.7e4.0) 2.8 (1.7e4.0) 0.0 (e1.0 to 1.1) .9571
Wk 8 5.5 (4.0e7.0) 3.8 (2.4e5.3) 1.7 (0.6e2.8) .0032
Wk 20 6.1 (4.4e7.9) 4.2 (2.5e6.0) 1.9 (0.8e2.9) .0008
Wk 32 6.4 (4.5e8.3) 4.3 (2.4e6.2) 2.1 (1.1e3.2) <.0001
Change from baseline in physical
domain of MENQOL, adjusted mean (95% CI)c
Wk 4 7.1 (4.7e9.6) 7.3 (4.9e9.7) e0.1 (e2.1 to 1.8) .9010
Wk 8 12.4 (9.1e15.8) 9.5 (6.2e12.9) 2.9 (0.7e5.1) .0105
Wk 20 14.1 (10.6e17.6) 10.1 (6.6e13.7) 4.0 (1.8e6.2) .0004
Wk 32 14.3 (10.7e18.0) 10.0 (6.4e13.6) 4.4 (2.2e6.5) <.0001
Change from baseline in sexual functioning
domain of MENQOL, adjusted mean (95% CI)c
Wk 4 0.9 (0.5e1.3) 0.8 (0.4e1.2) 0.1 (e0.5 to 0.6) .7985
Wk 8 1.5 (1.0e1.9) 1.2 (0.7e1.6) 0.3 (e0.3 to 0.9) .3400
Wk 20 1.4 (0.8e1.9) 1.2 (0.6e1.7) 0.2 (e0.4 to 0.8) .4910
Wk 32 1.5 (0.7e2.2) 1.0 (0.2e1.8) 0.5 (e0.1 to 1.1) .1360
Change from baseline in serum female
hormones, mean (95% CI)e
FSH, mIU/mL
Wk 8 4.1 (0.4e7.9) 2.0 (e1.8 to 5.9) 2.1 (e3.3 to 7.4) .4459
Wk 20 0.6 (e4.0 to 5.3) 0.4 (e3.7 to 4.6) 0.2 (e6.0 to 6.4) .9485
E2, pmol/L
Wk 8 e12.3 (e59.5 to 35.0) 19.5 (e38.5 to 77.6) e31.8 (e106.2 to 42.6) .4023
Wk 20 e2.3 (e58.7 to 54.1) e11.3 (e83.1 to 60.5) 8.9 (e82.5 to 100.4) .8467
LH, mIU/mL
Wk 8 0.9 (e1.3 to 3.2) 1.7 (e0.9 to 4.2) e0.7 (e4.1 to 2.7) .6769
Wk 20 e1.3 (e4.2 to 1.6) 0.1 (e2.6 to 2.8) e1.4 (e5.4 to 2.5) .4712
FSH/LH
Wk 8 0.2 (0.1e0.3) e0.1 (e0.3 to 0.0) 0.3 (0.1e0.5) .0024
Wk 20 0.2 (0.0e0.3) 0.0 (e0.1 to 0.1) 0.2 (0.0e0.4) .0499
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018. (continued)

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TABLE 2
Primary and secondary outcomesa (continued)

Electroacupuncture Sham electroacupuncture Between-group difference

Outcomes n ¼ 180 n ¼ 180 Value P value
Use of other treatment during study,
n(%)/value (95%CI)f,g
Wk 1e8 8 (4.6%) 8 (4.6%) 0.00 (e4.4 to 4.4) .9906
Wk 9e32 7 (4.1%) 9 (5.2%) 1.1 (e5.5 to 3.3) .6170
CI, confidence interval; E2, estradiol; FSH, follicle-stimulating hormone; HF, hot flash; LH, luteinizing hormone; MENQOL, Menopause-Specific Quality of Life Questionnaire; MRS, Menopause Rating
Scale.
a
MRS total and subscale scores, 24-h HF score, and MENQOL total and subscale scores were missing in 6 participants in electroacupuncture group and 5 participants in sham electroacupuncture
group at wk 4 and wk 8, and in 7 participants in electroacupuncture group and 6 participants in sham electroacupuncture group at wk 20 and wk 32eFSH, LH, and FSH/LH values were missing in 9
participants in electroacupuncture group and 8 participants in sham electroacupuncture group at wk 8, and in 16 participants in electroacupuncture group and 14 participants in sham elec-
troacupuncture group at wk 20eE2 values were missing in 37 participants in electroacupuncture group and 39 participants in sham electroacupuncture group at wk 8, and in 44 patients in
electroacupuncture group and 38 participants in sham electroacupuncture group at wk 20; b Number of participants with imputed data: 6 (3.3%), electroacupuncture group and 5 (2.7%), sham
electroacupuncture group; c Analyzed by fitting mixed effect model using baseline value as covariate, treatment as fixed effect, and site as random effect; d Secondary outcomes were performed in
observed cases, without imputation of missing data; e Analyzed using t test; f Analyzed using c2 test; g Other treatments mainly included hormone replacement therapy, antidepressants, and other
alternative therapies (vitamin E, clonidine, Chinese herbal medicine).
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018.

score at week 8 was 6.3 (95% CI,
5.0e7.7) in the EA group and 4.5 (95%
CI, 3.2e5.8) in the SA group with a
between-group difference of 1.8 (95%
CI, 0.9e2.8; P ¼ .0002). Similar
between-group differences were found
in the secondary outcomes of other MRS
total and subscale scores (except week 4)
(Table 2), subgroup analyses (Appendix
2, eTable 4), and the sensitivity analysis
using a control-based pattern-mixture
model (Appendix 2, eTable 2), but not
the sensitivity analysis using the worst-
case analysis (Appendix 2, eTable 3).
The EA group, as compared with the
SA group, seemed to have a greater
decrease in the mean 24-hour HF score
and the MENQOL total score and sub-
scale (except sexual functioning domain)
scores during weeks 8, 20, and 32 (not
during week 4). The between-group
differences for the decrease in the mean
24-hour HF score were 1.2 (95% CI,
0.6e1.8; P ¼ .0001) at week 8, 1.1 (95%
CI, 0.6e1.7; P < .0001) at week 20, and
2.2 (95% CI, 1.1e3.3; P <.0001) at week
32; the between-group differences for
the decrease in the MENQOL total score
were 5.7 (95% CI, 1.9e9.5; P ¼.0033) at
week 8, 7.1 (95% CI, 3.4e10.7; P ¼
.0002) at week 20, and 8.4 (95% CI,
4.8e12.0; P < .0001) at week 32.
Changes from baseline in FSH, LH,
and E2 levels at weeks 8 and 20 (P > .05
for all), with the exception of FSH/LH
ratios (P ¼.0024 at week 8 and 0.0499 at
week 20), did not differ between groups.
We did not find any difference between
groups in the use of other treatments
(P > .05).
There was no difference between
groups in the proportion of participants
who guessed EA when asked if they
received EA or SA treatment at week 4
and week 8 (P > .05 for both) (Table 3).
During the trial, 9 (5.0%) participants
in the EA group and 2 (1.1%) partici-
pants in the SA group (P > .05) had
treatment-related AEs that mainly
included severe needling pain and sub-
cutaneous hematoma in the EA group
and fatigue in the SA group (Table 4).
Nontreatment-related AEs were less
common (Appendix 2, eTable 5).
Comment
This randomized, controlled trial
demonstrated that reductions of MRS
total scores at weeks 8, 20, and 32 sup-
ported statistical but not clinical mean-
ingful differences between EA and SA on
the improvement of menopausal symp-
toms as the differences were all <5
points, the MCID.
Our findings partially support previ-
ous acupuncture studies in post-
menopausal and/or premenopausal
women that EA could decrease the MRS
(total or subscale) scores.9,24 In this trial,
the reductions of MRS score in the EA
group were 6.3 at week 8 and 6.8 at week
32, both greater than the MCID of 5
points.17 Nevertheless, the between-
group difference of 1.8 points of MRS
at week 8 (primary outcome), 2.4 points
during week 20, or 2.7 during week 32
was far less than the MCID of 5 points.
Our study thus supports the findings of
no clinical meaningful difference be-
tween EA and SA on menopausal
symptoms. The sensitivity analysis with
imputed missing data using control-
based pattern-mixture (between-group
difference: 1.7 points) was similar to our
primary endpoint analysis; whereas the
sensitivity analysis with imputed missing
data using the worst-case analysis (be-
tween-group difference: 0.4 point) was
far <1.8 of the primary outcome
(Appendix 2, eTables 2 and 3). The
discrepancy was consistent with the
conclusion that no clinical difference
between EA and SA on menopausal
symptoms was found in this trial.
HF are widely accepted as one of the
major menopausal symptoms.25,26 In
this trial, 24-hour HF score at week 8 was
reduced by 3.6 (50.7%) points in the EA
group, compared with 2.5 (42.4%) in the
SA group with a between-group differ-
ence of 1.2 points (P < .0001). In the
study by Pruthi et al,27 the reduction of
24-hour HF score was 4.9 for women
taking flaxseed and 3.5 for those on
placebo (P ¼.29). The sample size of this
trial differs from the study by Pruthi
et al27 (n ¼ 360 vs 188). Consequently,
the differences between treatment and

OCTOBER 2018 American Journal of Obstetrics & Gynecology 373.e7

Original Research GYNECOLOGY ajog.org

and 11th week) in both acupuncture and

TABLE 3
sham acupuncture groups for the MRS
Blinding assessment results
total and subscale scores and HF score,
Sham the between-group difference actually
Electroacupuncture electroacupuncture seemed to be decreased over time for HF
Treatment guess, n(%) n ¼ 174a n ¼ 175a P valueb score and more unequivocal for the MRS
Wk 4 Electroacupuncture 167 (96.0) 169 (96.6) .7694 scores.24 In another study, the score,
Sham 7 (4.0) 6 (3.4) frequency, and severity of HF decreased
electroacupuncture >4 weeks’ acupuncture treatment, but
Wk 8 Electroacupuncture 164 (94.3) 166 (94.9) .8035
stayed relatively the same at 3 and 6
months.12 These discrepancies may be
Sham 10 (5.8) 9 (5.1) caused by lengths of follow-ups, sham
electroacupuncture
a
acupuncture design, and number of
At 5 min after their last treatments of wk 4 and 8, participants were asked if they had received electroacupuncture or sham
electroacupuncture treatmenteduring study, 11 participants (6 from electroacupuncture group and 5 from sham electro-
acupuncture sessions.
acupuncture group) dropped out <wk 4; b c2 Test. The mechanism for the potential
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018. long-lasting effects of acupuncture on
women during MT remains unclear.
Most symptoms during MT are subjec-
control for 24-hour HF in the 2 studies between-group differences for the tive, associated with psychological stress.
are probably comparable, without a decrease in the MENQOL total score at Acupuncture is multimodal, involving
clinical meaningful difference. Both a weeks 8, 20, and 32 were all greater than practitioner-patient interaction; its psy-
50% mean reduction in the frequency of the MCID of 4 in the total MENQOL chological effects are unlikely to be
HF21 and a decrease of 5.35 episodes in score30; these results suggested that EA negligible. Experimental and clinical
moderate and severe HF per day from might improve quality of life for women studies have shown that placebo or sham
baseline have been reported as MCID.28 with MT. acupuncture is not inert.31 The possible
Similar to the results of MRS, the re- Interestingly, between-group differ- biophysiological effects of mechanical
ductions of 24-hour HF scores suggest ences in the change from baseline in the pressure from blunt needles at non-
that EA could alleviate symptoms of HF, total and subscale scores of MRS (not acupoints and EA at acupoints could be
but the effects are likely minimal when somatic-vegetative domain) and MEN- similar32,33; the visual and sensory sim-
considering MCID. QOL (not sexual functioning domain) ulations in the SA group might have
The MENQOL is a self-administered became stronger over time, but not in biological effects.34 These nonspecific or
instrument in assessing quality of life the mean 24-hour HF score. These re- placebo effects could be the causes of the
and its changes in women with meno- sults share similarities but meanwhile nonsignificant difference between verum
pausal symptoms.23 Its Chinese version differ from previous reports.12,24 and sham acupuncture in this
was found to have good psychometric Although changes from baseline trial.32,35,36
properties.29 In the present study, the increased over time (baseline, 7th week, To our knowledge, this is the first
trial of acupuncture for women during
MT. In this trial, we utilized blunt
TABLE 4 nonpenetrating needle at nonacupoints
Treatment-related adverse events as the sham control; the blinding effects
of this sham design were tested in a
Electroacupuncture Sham electroacupuncture
n ¼ 179a n ¼ 178a previous study.37 Traditionally, sham
acupuncture design includes shallow
Participants Events Participants Events
Adverse events n (%) n n (%) n needle insertion (minimal acupunc-
ture) and blunt needle without skin
Total 9 (5.0) 11 2 (1.1) 2
penetration at acupoints or non-
Dizziness 1 (0.6) 1 0 (0.0) 0 acupoints.38 Blunt needles at non-
Severe needling pain 4 (2.2) 5 0 (0.0) 0 acupoints without de qi in this trial
Subcutaneous 2 (1.1) 2 0 (0.0) 0 aimed to maximally decrease possible
hematoma acupuncture effect. In future acupunc-
Fatigue 1 (0.6) 1 2 (1.1) 2
ture studies, no treatment, waiting list,
or active treatment as the control may
Abdominal discomfort 1 (0.6) 2 0 (0.0) 0 be appropriate.
a
One participant in electroacupuncture group and 2 participants in sham electroacupuncture group did not receive Generalizability of the trial results
treatmenteadverse events were analyzed in all participants who received at least 1 session treatment.
Liu et al. Acupuncture for women in menopause transition. Am J Obstet Gynecol 2018. may be limited by the following factors:
mild baseline menopause symptoms

373.e8 American Journal of Obstetrics & Gynecology OCTOBER 2018

ajog.org
(mean baseline MRS total score: 17.0
and 16.7 out of 44 in the EA and SA
groups), MRS rather than HF score as
the main outcome, ethnically homoge-
nous study population (all Chinese),
lack of assessment of participants’ ex-
pectations,39 no stratified randomiza-
tion, or estimation of sample size
according to menopausal stage.
Conclusion
This trial did not support 8 weeks’ EA
treatment in relieving menopausal
symptoms in women during MT, even
though EA seemed to improve their
quality of life. Future studies should
focus on evaluating the efficacy of EA
for women with severe symptoms of
MT using reasonable control, and
address the relationship between partic-
ipants’ expectations and efficacy of
acupuncture. n 14. WHO Regional Office for the Western Pa-
Acknowledgment
We thank the volunteers for their participation.
We gratefully acknowledge Jiqian Fang, PhD
(Sun Yat-Sen University), for the guidance of
statistical analyses.
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Author and article information
From Guang’an Men Hospital (Drs Z. Liu, W. Wang, Y.
Wang, J. Zhou, L. Yang, Wu, and B. Liu), Institute of Basic
Research in Clinical Medicine (Drs Ai, He, Y. Liu, Yan, and
J. Liu), and Institute of Acupuncture and Moxibustion (Dr
Xu), China Academy of Chinese Medical Sciences, Bei-
jing, China; Catholic Health System Internal Medicine
373.e10 American Journal of Obstetrics & Gynecology OCTOBER 2018
Training Program, University at Buffalo, Buffalo, NY (Dr K.
Zhou); Yueyang Hospital of Integrated Traditional Chinese
and Western Medicine affiliated with Shanghai University
of Traditional Chinese Medicine, Shanghai, China (Dr
Dong); Third Affiliated Hospital of Zhejiang Chinese
Medical University, Hangzhou, China (Dr Fang); Guang-
dong Province Hospital of Traditional Chinese Medicine,
Guangzhou, China (Dr Fu); Shaanxi Province Hospital of
Traditional Chinese Medicine, Xi’an, China (Dr Su); Hos-
pital of Integrated Chinese and Western Medicine, Shanxi
University of Traditional Chinese Medicine, Taiyuan,
China (Dr J. Wang); Affiliated Hospital of Shandong Uni-
versity of Chinese Medicine, Jinan, China (Dr R. Wang);
First Affiliated Hospital of Anhui University of Chinese
Medicine, Hefei, China (Dr J. Yang); Hengyang Hospital
affiliated with Hunan University of Chinese Medicine,
Hengyang, China (Dr Yue); Yantai Hospital of Traditional
ajog.org
Chinese Medicine, Yantai, China (Dr Zang); First Hospital
of Hunan University of Chinese Medicine, Changsha,
China (Dr Zhang); and Hubei Provincial Hospital of
Traditional Chinese Medicine, Wuhan, China (Dr Z. Zhou).
Received April 9, 2018; revised July 22, 2018;
accepted Aug. 10, 2018.
This study was supported by the program of the 12th
five-year National Science and Technology Pillar Program
(2012BAI24B01; 2012BAI24B02) by the Ministry of
Science and Technology of the People’s Republic of
China.
All authors have completed and submitted the Inter-
national Committee of Medical Journal Editors uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and
declare no conflicts of interest.
Corresponding author: Baoyan Liu, MD.
baoyanjournal@163.com