Acupuncture for polycystic ovarian syndrome

Abstract

Background
This systematic review aimed at summarizing and evaluating the evidence from randomized controlled trials (RCTs) using acupuncture to treat polycystic ovarian syndrome (PCOS), specifically focusing on ovulation rate, menstrual rate, and related hormones.

Methods
Fifteen databases were searched electronically through February 2016. Our review included RCTs of women with PCOS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. Two reviewers independently extracted data. Data were pooled and expressed as mean differences (MDs) for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals (CIs) using a random-effects model.

Results
We found a low level of evidence that acupuncture is more likely to improve ovulation rate (MD 0.35, 95% CI: 0.14–0.56) and menstruation rate (MD 0.50, 95% CI: 0.32–0.68) compared with no acupuncture. We found statistically significant pooled benefits of acupuncture treatment as an adjunct to medication in luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, fasting insulin, and pregnancy rates, but the level of evidence was low/very low.

Conclusion
There is limited evidence to judge the efficacy and safety of acupuncture on key reproductive outcomes in women with PCOS. Large-scale, long-term RCTs with rigorous methodological input are needed.

Full text

Acupuncture for polycystic ovarian syndrome
A systematic review and meta-analysis
Junyoung Jo, KMD, PhD
a
, Yoon Jae Lee, KMD, PhD
b
, Hyangsook Lee, KMD, PhD
c,d,∗
Abstract
Background: This systematic review aimed at summarizing and evaluating the evidence from randomized controlled trials (RCTs)
using acupuncture to treat polycystic ovarian syndrome (PCOS), specifically focusing on ovulation rate, menstrual rate, and related
hormones.
Methods: Fifteen databases were searched electronically through February 2016. Our review included RCTs of women with
PCOS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. Two reviewers independently
extracted data. Data were pooled and expressed as mean differences (MDs) for continuous outcomes and risk ratios for
dichotomous outcomes, with 95% confidence intervals (CIs) using a random-effects model.
Results: We found a low level of evidence that acupuncture is more likely to improve ovulation rate (MD 0.35, 95% CI: 0.14–0.56)
and menstruation rate (MD 0.50, 95% CI: 0.32–0.68) compared with no acupuncture. We found statistically significant pooled
benefits of acupuncture treatment as an adjunct to medication in luteinizing hormone (LH), LH/follicular stimulating hormone (FSH)
ratio, testosterone, fasting insulin, and pregnancy rates, but the level of evidence was low/very low.
Conclusion: There is limited evidence to judge the efficacy and safety of acupuncture on key reproductive outcomes in women
with PCOS. Large-scale, long-term RCTs with rigorous methodological input are needed.
Abbreviations: BMI =body mass index, CC =clomiphene citrate, CHM =Chinese herbal medicine, CI =confidence interval, EA
=electroacupuncture, FSH =follicular stimulating hormone, GRADE =Grading of Recommendations, Assessment, Development
and Evaluation, LH =luteinizing hormone, MD =mean difference, PCOS =polycystic ovarian syndrome, RCT =randomized
controlled trial.
Keywords: acupuncture, menstrual cycle, meta-analysis, ovulation, polycystic ovarian syndrome, randomized controlled trial
1. Introduction
Polycystic ovarian syndrome (PCOS) is diagnosed on the basis of
oligo-ovulation or anovulation, hyperandrogenism, and the
presence of polycystic ovaries.
[1]
The prevalence of PCOS is as
high as 15% when the Rotterdam criteria are applied.
[2]
PCOS is
estimated to account for 70% to 90% of ovulatory disorders.
[3]
No single etiologic factor fully accounts for the spectrum of
abnormalities in PCOS.
[4]
The most obvious neuroendocrine
feature in PCOS is increased luteinizing hormone (LH) pulsatility,
with relatively low follicular stimulating hormone (FSH)
secretion.
[5]
One of the common features of PCOS is insulin
resistance, reported in 62% to 95% of women with PCOS.
[6]
Elevated androgen level, another common feature of PCOS,
affects around 60% to 80% of women with PCOS and can
produce clinical signs like hirsutism, acne, and alopecia.
[7]
Clomiphene citrate (CC), a selective estrogen-receptor modula-
tor, has been used as 1st-line treatment for PCOSfor decades.
[8]
CC
is not without drawbacks, however, including its overall poor
efficacy, a relatively high multiple-pregnancy rate (3%–8%), and
side effects such as mood changes and hot flushes.
[8]
Acupuncture involves the insertion of needles into specific
anatomical points (termed acupoints) and has been used in
eastern Asian countries for thousands of years. Recently, the use
of acupuncture in reproductive endocrinology and infertility has
gained increased popularity worldwide.
[9]
Several clinical and
animal experimental studies indicate that acupuncture is
beneficial for ovulatory dysfunction in PCOS.
[5]
Acupuncture
has also been reported to potentially improve insulin sensitivity
and to decrease testosterone in patients with PCOS.
[10,11]
Editor: Dennis Enix.
JJ and YJL contributed equally to this work.
Authorship: JJ and YJL equally contributed to this work; JJ and YJL are
responsible for the study concept, design, and literature searching; JJ, YJL, and
HL are responsible for data analysis and interpretation; JJ, YJL, and HL drafted
the paper; HL supervised the study; and all authors participated in the analysis
and interpretation of data and approved the final manuscript.
Details of ethics approval: No ethical approval was required for this systematic
review and meta-analysis.
Funding/support: This work was supported by the Korea Institute of Oriental
Medicine (KIOM, grant No. 20170244) and the National Research Foundation
(NRF) of Korea funded by the Korean government (Ministry of Science, ICT &
Future Planning, grant No. NRF-2014R1A1A2055507).
The authors have no conflicts of interest to disclose.
Supplemental Digital Content is available for this article.
a
Department of Korean Gynecology, Conmaul Hospital of Korean Medicine,
b
Department of Korean Gynecology, Jaseng Hospital of Korean Medicine,
c
Acupuncture and Meridian Science Research Center, College of Korean
Medicine, Kyung Hee University, Seoul, Korea,
d
Australian Research Center in
Complementary and Integrative Medicine, Faculty of Health, University of
Technology Sydney, Sydney, Australia.
∗
Correspondence: Hyangsook Lee, Acupuncture and Meridian Science Research
Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
(e-mail: erc633@khu.ac.kr).
Copyright ©2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Medicine (2017) 96:23(e7066)
Received: 9 December 2016 / Received in final form: 11 April 2017 / Accepted:
10 May 2017
http://dx.doi.org/10.1097/MD.0000000000007066
Systematic Review and Meta-Analysis Medicine®
OPEN
1

Recently, several systematic reviews on acupuncture for PCOS
were published.
[12–14]
However, there are some discrepancies
among these studies and outcomes. The 1st meta-analysis by Qu
et al (2016) focused on the recovery of menstrual cycles and
hormone levels, but it was based on only 9 randomized controlled
trials (RCTs) with a total of 531 participants. The 2nd review by
Wu et al (2016) looked at 31 RCTs with 2371 subjects, but it did
not attempt a meta-analysis. The 3rd Cochrane review by Lim
et al (2016) included only 5 RCTs with 413 participants and
focused on live birth and ovulation only. Thus, no one review
comprehensively included all the available studies nor performed
meta-analyses of important outcomes including menstruation
cycles, pregnancy, and hormonal changes.
Therefore, this systematic review aimed at summarizing and
evaluating the currently available evidence from RCTs of
acupuncture to treat PCOS, specifically focusing on ovulation
rate, menstrual rate, and related hormones.
2. Materials and methods
The protocol for this systematic review was registered
(CRD42015016485) and the review was conducted and reported
as outlined in the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses statement.
[15]
2.1. Search strategies
We searched databases for relevant studies published through
February 2016, comprising 4 international, 3 Chinese, 6 Korean,
and 2 Japanese databases. The detailed search strategies are
provided in Appendix S1, http://links.lww.com/MD/B720.
References of relevant publications (eg, gynecology textbooks,
complementary and alternative medicine textbooks, clinical
guidelines, or reviews of infertility) were also hand-searched.
No language restrictions were imposed.
2.2. Study selection
Our review included RCTs of women with PCOS; these RCTs
compared acupuncture with sham acupuncture, medication, or
no treatment. The detailed study selections are provided in
Appendix S2, http://links.lww.com/MD/B720.
2.3. Data extraction
All studies were reviewed and selected independently by 2
reviewers (JJ and YJL). The titles and abstracts were reviewed and
articles that did not fit the eligibility criteria were excluded. If the
title or abstract appeared to meet the eligibility criteria, the full-
texts of the articles were obtained for further evaluation.
Discrepancies between the reviewers were resolved by consensus
among all 3 reviewers. The independent reviewers extracted and
tabulated data using a standardized data extraction form, with
disagreements resolved by discussion with the corresponding
author (HL). The form included information pertaining to first
author, study design, quality of methods, language of publica-
tion, country where the trial was conducted, inclusion/exclusion
criteria, PCOS diagnostic criteria used, number of participants
allocated to each group, acupuncture intervention details,
comparison groups, outcome measures, follow-up periods, and
reported adverse events associated with acupuncture. When
studies reported outcomes at more than 1 time point, a similar
measurement point in other studies was taken for analysis. If the
data in an article were insufficient or ambiguous, 1 author (YJL)
contacted the corresponding author by e-mail to obtain further
information.
2.4. Risk of bias assessment
We evaluated the risk of bias among the included studies using
the risk of bias assessment tool by the Cochrane Collabora-
tion.
[16]
The criteria consist of 7 items related to selection bias
(random sequence generation and allocation concealment),
performance bias (blinding of participants and personnel),
detection bias (blinding of outcome assessment), attrition bias
(incomplete outcome data), reporting bias (selective outcome
reporting), and other source of bias. Each study was assigned
“yes”for a low risk of bias, “no”for a high risk of bias, or
“unclear”for an unclear risk of bias for each item. Any
discrepancies between the 2 authors were resolved by discussion
with the corresponding author (HL) until consensus was reached.
2.5. Data synthesis
Statistical analyses were performed with the Review Manager
program (Version 5.3 Copenhagen: The Nordic Cochrane
Centre, The Cochrane Collaboration, 2014) and Stata (Stata-
Corp 2015; Release 14. College Station, TX: StataCorp LP).
Trials were combined according to the type of intervention,
outcome measure, and/or control. Data were pooled and
expressed as mean difference (MD) for continuous outcomes
and risk ratio for dichotomous outcomes with 95% confidence
intervals (CIs) using a random-effects model to incorporate
expected heterogeneity. Heterogeneity among studies was
assessed using x
2
test with a significance level of P<.1 and I
2
statistic.
[17]
The I
2
statistic indicates the proportion of variability
among trials that is not explained by chance alone and we
considered an I
2
value >50% to indicate a substantial
heterogeneity.
[17,18]
If a substantial heterogeneity was detected,
we explored sources of heterogeneity by subgroup analysis.
Subgroup analyses were attempted according to type of control
(eg, medication type). If some factor (eg, large methodological
and/or clinical difference among trials) was found, we did not
conduct subgroup analysis or data synthesis, but reported a
narrative description of the included studies. When there were
more than 10 trials in the analysis, reporting biases such as
publication bias were assessed by funnel plots. If asymmetry is
suggested by a visual inspection, we performed exploratory
analyses using Egger method.
[17]
2.6. Dealing with missing data
As much as possible, data were analyzed using an intention-to-
treat basis, and attempts were made to obtain missing data from
the original investigators. When these attempts were not
successful, we did not impute data for missing data, but only
analyzed available data.
2.7. Level of evidence
Grading of Recommendations, Assessment, Development and
Evaluation (GRADE) was used to assess the level of evidence and
summarize each outcome.
[19]
The level of evidence was
categorized into 4 levels: high, moderate, low, or very low
quality. The GRADE pro software (version 3.6.1 for Windows,
Grade Working group) was used.
Jo et al. Medicine (2017) 96:23 Medicine
2

3. Results
Our initial search identified 1179 records, of which 1024 articles
were screened. We excluded 887 articles based on the title and
abstract, and retrieved 137 articles for more detailed evaluation.
Of these, 27 RCTs were included (Fig. 1).
[15]
3.1. Characteristics of the included studies
3.1.1. Study design. Of 27 studies, 23 originated from China
and were all published in Chinese
[20–41]
except 1 trial that was
published in English.
[42]
Two studies were performed in
Sweden,
[10,43]
1 in America,
[44]
and 1 in Australia and China.
[45]
Although 7 articles
[21,22,33,36–38,40]
were master’s theses, 20
studies were published in peer-reviewed journals.
3.1.2. Participants. A total of 2093 participants were enrolled in
the 27 studies with sample sizes ranging from 25 to 251.
Calculations of sample size and statistical power were reported in
only 3 studies.
[10,43,44]
All participants were diagnosed with
PCOS according to Rotterdam criteria.
[1]
Eight trials involved
women with PCOS and subfertility together.
[20–22,31,32,34,36,38]
Although 7 studies were conducted only in patients with obesity-
Figure 1. PRISMA flow diagram of literature searching and article selection process. ∗From 3-arm study. PCOS =polycystic ovarian syndrome, PRISMA =
Preferred reporting items for systematic reviews and meta-analyses, RCT=randomized controlled trials, Sham =sham acupuncture.
Jo et al. Medicine (2017) 96:23 www.md-journal.com
3

type PCOS (body mass index (BMI) ≥25kg/m
2
),
[20,26,32,34,37,41,42]
7 did not report BMI.
[20,21,25,30,31,39,40]
Baseline characteristics
among groups were reported as comparable in each study.
3.1.3. Interventions. Twelve trials tested the effectiveness of
acupuncture alone
[10,20,24,29–31,37,42–45]
and the others used
acupuncture as an adjunct to CC,
[21,22,28,33,35,36,38]
Chinese
herbal medicine (CHM),
[26,27,40]
metformin,
[20,32]
Diane-35, or
combinations of these.
[15,25,34,39,41]
Nineteen trials used manual
acupuncture
[20–22,25–32,34–36,39–42,45]
and the others used manual
acupuncture with electrical stimulation, that is, electroacupunc-
ture (EA).
[10,20,24,33,37,38,43,44]
Acupuncture interventions varied
in acupoint selection, frequency of treatment, and number of
treatment sessions across studies. The duration of therapy ranged
from 10 weeks to 6 months. The characteristics of the included
studies are presented in Table 1 and more detailed information on
acupuncture interventions are provided in Table S1, http://links.
lww.com/MD/B721.
3.1.4. Outcomes. For primary outcomes, 2 studies reported
ovulation rate
[10,44]
and another 2 studies reported menstruation
rate.
[42,43]
For secondary outcomes, LH,
[10,20,21,24–27,29–35,37,39,40,42–44]
LH/FSH ratio,
[10,20–22,24–27,29,31,32,34,37,39,41–44]
testosterone,
[10,20–22,24–35,37,39–43]
fasting insulin levels,
[10,20,25,26,29,33,34,37,41,42]
and pregnancy rate
[21,28,31,33,34,36,38,41,44,45]
were reported. One
study
[28]
established pregnancy by blood and urine human chorionic
gonadotropin testing. Another study
[36]
determined pregnancy by
ultrasound. In 2 studies,
[44,45]
pregnancy was established by
participant self-report. Six studies
[21,31,33,34,38,41]
did not document
clearly the diagnostic criterion (ie, biochemical or clinical) for
pregnancy. Eleven studies reported adverse events.
[20–22,24,29,31,33,36,
42–44]
In 7 of the 11 studies, no adverse events were reported in patients
receiving acupuncture.
[20,21,24,29,31,36,42]
Sixteen studies did not report
adverse events.
[10,20,25–28,30,32,34,35,37–41,45]
3.2. Risk of bias in the included studies
A summary of the risks of bias is provided in Fig. 2 and the
authors’judgments on risk of bias are provided in Appendix S3,
http://links.lww.com/MD/B720.
3.3. Effects of acupuncture
We summarized the outcomes according to the following
categories, based on the type of control group: acupuncture
versus sham acupuncture; acupuncture versus no treatment;
acupuncture versus medication; acupuncture with medication
versus sham acupuncture with medication; and acupuncture with
medication versus medication alone (Table 2).
3.3.1. Acupuncture versus sham acupuncture (4 studies).
Outcomes: There were no studies that reported menstruation
rate. There was evidence of an improvement in fasting insulin
levels between women who received true versus sham acupunc-
ture (MD 3.43, 95% CI 6.25 to 0.61, P=.02).
[37]
There
were no significant differences in other outcomes (Table 2).
Adverse events: One study
[44]
reported 1 participant having a
back spasm during an acupuncture session, and a subsequent
evaluation by a physician outside the study team determined that
the spasm was unrelated to the treatment. The others
[20,37,45]
did
not report adverse events.
3.3.2. Acupuncture versus no treatment (2 studies). Out-
comes: There was evidence of improvement in ovulation rates,
monthly menstruation rates, and testosterone levels in the
acupuncture group compared to no treatment (Table 2).
[10,43]
There were no studies that reported pregnancy rate. No
significant differences in other outcomes emerged (Table 2).
Adverse events: One study
[43]
mentioned that 3 participants
had adverse events (isolated redness and subsequent hematomas)
after 1 of the 14 low-frequency EA treatments. One participant
reported dizziness and 1 reported nausea after 1 low-frequency
EA treatment. No long-term adverse events occurred in the low-
frequency EA group. Another study
[10]
did not report adverse
events.
3.3.3. Acupuncture versus medication (6 studies). Outcomes:
There were no studies that reported ovulation rate. There was
evidence of an improvement in monthly menstruation rates in
women who received acupuncture compared to those who
received metformin (MD 0.14, 95% CI 0.05 to 0.23,
P=.003).
[42]
The pooled results from 6 studies
[22,24,29–31,42]
showed no significant difference in testosterone levels between
the acupuncture and medication groups (MD 0.04, 95% CI
0.11 to 0.03, P=.30, I
2
=93%) with considerable heterogene-
ity. We conducted a subgroup analysis according to the control
type, and the pooled results from 2 studies
[29,42]
comparing
acupuncture with metformin showed a significant difference in
testosterone levels in the acupuncture group compared to the
medication group (MD 0.13, 95% CI 0.21 to 0.05,
P=.002, I
2
=0%, Fig. S1, http://links.lww.com/MD/B721).
There were no significant differences in other outcomes (Table 2).
Adverse events: All but 1 study
[30]
reported adverse events.
One patient in the Diane-35 group
[24]
had a gastrointestinal
problem, while no adverse events occurred in the acupuncture
group. Metformin groups from 2 studies
[29,42]
reported gastro-
intestinal problems such as nausea, vomiting, and diarrhea,
whereas no adverse events occurred in the acupuncture group.
Four patients among 30 who received CC treatment
[31]
reported
mild nausea, but no adverse events occurred in the acupuncture
group. In another study,
[22]
2 among 30 patients had mild
bleeding at the site of needling in the acupuncture group, and 5
patients among 28 in the CC group had gastrointestinal
problems.
3.3.4. Acupuncture with medication versus sham acupunc-
ture with medication (4 studies). Outcomes: There were no
studies that reported ovulation rates and monthly menstruation
rates (per woman). There was evidence of an improvement in LH
levels, LH/FSH ratios,
[20,32]
and fasting insulin levels
[20]
in the
true acupuncture with medication group compared to the sham
acupuncture with medication group (Table 2). The pooled results
from 3 studies
[20,32,35]
showed a significant difference in LH
levels in the true acupuncture with medication group compared
to the sham acupuncture with medication group (MD 1.82,
95% CI 3.44 to 0.21, P=.03, I
2
=94%, Table 2). When we
conducted a subgroup analysis according to the control
medication type, acupuncture plus metformin
[20,32]
showed a
significant difference in LH levels compared with sham
acupuncture with metformin (MD 0.99, 95% CI 1.35 to
0.63, P<.00001, I
2
=0%, Fig. S2, http://links.lww.com/MD/
B721). The pooled results in testosterone levels
[20,32,35]
showed a
marginally significant difference between true acupuncture with
medicine and sham acupuncture with medicine (MD 0.10, 95%
CI 0.20 to 0.00, P=.06, I
2
=94%, Table 2). A subgroup
analysis revealed that true acupuncture with metformin
[20,32]
also
showed a marginally significant difference in testosterone levels
Jo et al. Medicine (2017) 96:23 Medicine
4

Table 1
Characteristics of the included studies.
Study Country
Number of
participants
Mean
age, y Acupuncture Control
Acupuncture
session
Outcomes (primary/
secondary)
Acupuncture versus sham acupuncture
Pastore et al (2011) USA EG: 40, CG: 44 EG: 28.0 (6.3),
CG: 26.5 (5.8)
EA SA Total 12 times over 2 mo Ovulation rate/LH, LH/FSH ratio,
pregnancy rate, adverse
events
Guo (2014) China EG: 20, CG: 20 EG: 27.8 (3.2),
CG: 29.3 (2.9)
EA SA Daily or every other day for
2mo
NR/LH, LH/FSH ratio, FI, T
Zhao et al (2014) China EG: 24, CG: 24 EG: 26.0 (3.5),
CG: 26.0 (3.8)
EA SA Every other day for 4 mo NR/LH, LH/FSH ratio, T
Lim et al (2014) Australia and
China
EG: 98, CG: 48 EG: 26.1 (4.2),
CG: 25.1 (3.0)
MA SA Weekly for 3 mo NR / pregnancy rate
Acupuncture vs no treatment
Jedel et al (2011) Sweden EG: 33, CG: 17 EG: 29.7 (4.3),
CG: 30.1 (4.2)
EA No treatment Total 14 times over 4 mo Monthly menstruation rate/LH,
LH/FSH ratio, T, adverse
events
Johansson et al (2013) Sweden EG: 16, CG: 16 EG: 28.4 (3.1),
CG: 27.9 (3.2)
EA No treatment Twice weekly for 10–13
wk
Ovulation rate/LH, LH/FSH ratio,
T, FI
Acupuncture vs medication
Cui et al (2012) China EG: 30, CG: 30 NR MA Diane-35 Every other day except
period for 3 mo
NR/LH, T
Lai et al (2012) China EG: 60, CG: 60 EG: 26.7 (2.7),
CG: 26.5 (2.7)
MA Met Every other day except
period for 4 mo
NR/LH, LH/FSH ratio, T, FI,
adverse events
Zheng et al (2013) China EG: 43, CG: 43 EG: 26.5 (3.0),
CG: 24.9 (4.9)
MA Met Total 48 times over 6 mo Menstrual frequency/LH, LH/FSH
ratio, T, FI, adverse events
Jin et al (2014) China EG: 33, CG: 32 EG: 29.0 (4.0),
CG: 27.0 (5.0)
EA Diane-35 Total 36–40 times, 3
times weekly except
period
NR/LH, LH/FSH ratio, T, adverse
events
Ma (2014)
∗
China EG: 30, CG: 30 EG: 24.4 (3.3),
CG: 25.1 (3.9)
MA CC Total 36 times over 3 mo,
3 times weekly except
period
NR/LH/FSH ratio, T, adverse
events
Yuan et al (2010) China EG: 30, CG: 30 NR MA CC Daily for 3 d and every
other day for 3 d except
period for 3 mo
NR/LH, LH/FSH ratio, T,
pregnancy rate, adverse
events
Acupuncture added to medication vs sham acupuncture with medication
Li et al (2014) China EG: 53, CG: 51 EG: 27.1 (2.5),
CG: 25.2 (1.8)
MA + Met SA+ Met Daily except period for 6
mo
NR/LH, LH/FSH ratio, T, FI,
adverse events
Li et al (2015) China EG: 75, CG: 75 EG: 25.1 (2.3),
CG: 24.1 (2.2)
MA + Met SA+ Met NR specifically, for 6 mo NR/LH, LH/FSH ratio, T
Gu (2014) China EG: 16, CG: 9 EG: 28.4 (3.2),
CG: 26.4 (3.3)
EA + CC SA + CC Total 32 times over 4 mo NR/pregnancy rate
Liao et al (2014) China EG: 30, CG: 30 NR MA + CC SA + CC Total 32 times over 4 mo NR/LH, T
Acupuncture added to medication vs medication alone
Zhao et al (2007) China EG: 30, CG: 30 EG: 26.8 (3.4),
CG: 27.5 (3.6)
MA + Met + CC Met + CC NR specifically NR/LH/FSH ratio, T, FI, pregnancy
rate
Wang et al (2012) China EG: 126, CG: 125 EG: 25.2 (5.1),
CG: 25.6 (6.1)
MA + CHM + Met
+ Diane-35
CHM + Met +
Diane-35
Every 3 d except period NR/LH, LH/FSH ratio, T, FI
Pan (2015) China EG: 15, CG: 15 EG: 24.3 (7.9),
CG: 22.2 (8.8)
MA + CHM CHM Total 30 times over 2 mo NR / LH, T
Su et al (2013) China EG: 40, CG: 40 EG: 25.7 (5.0),
CG: 28.2 (5.2)
MA + CHM CHM Every other day for 3 mo NR/LH, LH/FSH ratio, T, FI
Li et al (2013) China EG: 26, CG: 26 EG: 29.1 (3.2),
CG: 28.2 (4.2)
MA + CHM CHM 5 d a week for 3 mo NR/LH, LH/FSH ratio, T
Ji et al (2013) China EG: 40, CG: 40 EG: 23.3 (3.2),
CG: 29.5 (4.9)
MA + CC CC Daily for 3 d and every
other day for 3 d except
period for 3 periods
NR/T, pregnancy rate
Zhang (2013) China EG:30, CG: 30 EG: 24.4 (2.7),
CG: 25.6 (2.0)
MA + Met +
Diane-35
Met + Diane-35 NR specifically NR/LH, T
Ma (2014)
∗
China EG: 30, CG: 30 EG: 23.5 (2.4),
CG: 25.1 (3.9)
MA + CC CC Total 36 times over 3 mo,
3 times weekly except
period
NR/LH/FSH ratio, T, adverse
events
Sun (2014) China EG: 30, CG: 30 EG: 29.6 (3.9),
CG: 28.7 (4.2)
MA + CC CC Every other day except
period for 3 mo
NR/LH, T, pregnancy rate,
adverse events
Yang (2014) China EG: 30, CG: 30 EG: 30.0 (4.4),
CG: 29.3 (4.2)
MA + CC CC Total 32 times over 4 mo NR/pregnancy rate, adverse
events
Liang et al (2015) China EG: 40, CG: 40 EG: 28.6 (3.2),
CG: 27.8 (3.3)
MA + CC + CHM CC + CHM NR specifically, for 3 mo NR/LH, LH/FSH ratio, T, FI,
pregnancy rate
Chen (2015) China EG: 30, CG: 30 EG: 27.9 (4.4),
CG: 28.0 (4.2)
EA + CC CC Total 32 times over 4 mo NR/LH, T, FI, pregnancy rate,
adverse events
CC =clomiphene citrate, CG =control group, CHM =Chinese herbal medicine, EA=electroacupuncture, EG=experimental group, FI =fasting insulin, FSH =follicu lar stimulating hormone, LH =luteinizing
hormone, MA =manual acupuncture, Met =metformin , NR =not reported, SA =sham acupuncture, T =testosterone.
∗
Ma (2014) study had 2 acupuncture arms, that is, acupuncture only group and acupuncture plus medication group.
Jo et al. Medicine (2017) 96:23 www.md-journal.com
5

compared with sham acupuncture with metformin (MD 0.05,
95% CI 0.10 to 0.00, P=.04, I
2
=54%, Fig. S2, http://links.
lww.com/MD/B721). There was no evidence of a difference
in pregnancy rates compared with sham acupuncture with CC
(Fig. S2, http://links.lww.com/MD/B721).
Adverse events: One study
[20]
reported that 22 patients
(43.14%) in the sham acupuncture with metformin group had
nausea or vomiting, mild diarrhea, and slight dizziness or
weakness, while 18 patients (33.96%) in the true acupuncture
with metformin group experienced these events. Three stud-
ies
[32,35,37]
did not report adverse events.
3.3.5. Acupuncture with medication versus medication
alone (12 studies). Outcomes: There were no studies that
reported ovulation rates and monthly menstruation rates
(per woman). There was evidence of an improvement in LH
levels, LH/FSH ratios, testosterone levels, fasting insulin
levels,
[25,26,33,34,41]
and pregnancy rates
[21,28,33,34,36,41]
(Table 2).
The pooled results
[21,25–27,33,34,39,40]
showed a significant
improvement in LH levels in the true acupuncture with
medication group compared with the medication alone group
(MD 1.40, 95% CI 2.54 to 0.25, P=.02, I
2
=91%). A
subgroup analysis according to the control group revealed that
acupuncture added to combined medication (CHM plus CC),
[34]
(CHM plus metformin and Diane-35),
[25]
(metformin with
Diane-35)
[39]
only showed a significant difference in LH levels
when compared with combined medication alone (MD 1.88,
95% CI 2.55 to 1.21, P<.00001, I
2
=47%, Fig. S3, http://
links.lww.com/MD/B721). The pooled results showed acupunc-
ture produced a significant improvement in LH/FSH ratios
[21,22,25–27,34,39,41]
and testosterone levels
[21,22,25–28,33,34,39–41]
with considerable heterogeneity (Fig. S3, http://links.lww.com/
MD/B721). We conducted a subgroup analysis according to the
control group, but heterogeneity was not resolved.
Adverse events: One study
[33]
reported that 1 patient among 30
in the acupuncture group had mild pain at the site of needling. In
another study,
[22]
3 among 29 patients had mild bleeding at the
site of needling in the acupuncture combined with CC group, and
5 patients among 28 in the CC group had gastrointestinal
problems, whereas there were no gastrointestinal problems in the
acupuncture group. Two studies
[21,36]
reported that there were
no serious adverse events. Eight studies
[25–28,34,39–41]
did not
report adverse events.
3.4. Levels of evidence
The levels of evidence as determined by GRADE were found to be
from very low to low (Table 2). Most of the studies were classified
as having either an unclear or a high risk of selection bias,
performance bias, and attrition bias, so all outcomes were
initially downgraded in risk of bias domain. In addition, all
outcomes were downgraded in the imprecision domain, due to
small sample size that was far from optimal information size. The
inconsistency domain was downgraded for unexplained hetero-
geneity in the outcomes: LH levels, LH/FSH ratios, and
testosterone levels in the acupuncture versus sham acupuncture
group; LH levels in the acupuncture versus no treatment group;
LH levels, testosterone levels in the acupuncture versus
medication group, LH levels, LH/FSH ratios, testosterone levels
in the acupuncture plus medication versus sham acupuncture plus
medication group; and LH levels, LH/FSH ratios, testosterone
levels in the acupuncture plus medication versus medication
alone group (Table 2).
4. Discussion
4.1. Summary of main findings
The objective of this review was to summarize and evaluate
acupuncture treatment to improve ovulation and menstruation
rates and other hormonal changes, in women with PCOS.
We found a low level of evidence that acupuncture is more
likely to improve ovulation and menstruation rates compared to
not receiving acupuncture. When compared with metformin,
acupuncture improves menstruation rates but the level of
Figure 2. Risk of bias assessed using the Cochrane “Risk of bias”tool. +, High
risk of bias; ?, unclear risk of bias; and , low risk of bias.
Jo et al. Medicine (2017) 96:23 Medicine
6

evidence is also low. We found statistically significant benefits of
acupuncture treatment for up to 4 months as an adjunct to
medication, seen in LH levels, LH/FSH ratios, testosterone levels,
fasting insulin, and pregnancy rates, but the level of evidence
is very low or low, mainly due to high risk of bias and
heterogeneity. To date the evidence on acupuncture for PCOS
remains largely inconclusive as the studies we reviewed tested
different acupuncture protocols against various control types and
the reported outcomes varied greatly. Acupuncture seems to be
associated with few adverse events. Reported adverse events,
such as needling pain, were mild and transient; there were no
serious adverse events leading to withdrawals from the study.
4.2. Applicability of the current evidence
The included studies poorly addressed ovulation and menstrua-
tion rates, the primary outcomes in our review. Only 4 among 27
studies reported ovulation and/or menstruation rates. We found
that acupuncture significantly improved monthly menstrual rates
in comparison with no treatment or medication only, while
ovulation rates were significantly improved by acupuncture only
when it was compared with no treatment, but not with sham
acupuncture. There may be 2 different interpretations for this.
Acupuncture works mainly via a placebo effect
[46]
; or the
adopted sham acupuncture control may not be completely
inert.
[5,44,47]
It is premature to determine which interpretation is
valid as there are too few studies to make an evidence-based
decision.
The optimal acupuncture treatment is a complex issue
involving a range of contributing factors,
[48]
for example,
number of sessions, acupoint specificity and selection, stimula-
tion methods, and the practitioner’s expertise. In the study
comparing acupuncture with a sham control where no difference
was detected in ovulation rates,
[44]
women received 12
acupuncture sessions over 8 weeks and the needle placement
and stimulation was identical in both true and sham acupuncture
groups. In another study,
[10]
where needles were placed similarly
as in the previous study,
[44]
women received acupuncture twice
weekly during the study period, thus an increased dose of
acupuncture treatment was tested. Women allocated to the
acupuncture group had a higher ovulation frequency compared
with the no treatment group, indicating a dose–response effect as
well as an augmented acupuncture effect.
[5]
This tendency was
more evident in other study
[20]
where acupuncture treatment was
conducted every other day for 4 months. This suggests that
different acupuncture doses exert different treatment effects, and
therefore, exploring the optimal acupuncture treatment interven-
tion for PCOS should be preconditions of any future trials.
Although limited by heterogeneity across studies, we found
that acupuncture adjuvant to other active medications could
Table 2
Meta-analysis of outcomes and level of evidence.
Variable
Overall effect
Studies (N) Sample size (N) Level of evidence
MD 95% CI PI
2
PStatistical method
Acupuncture versus sham acupuncture
Ovulation rate 0.03 0.15, 0.09 .62 ––Random inverse variance 1 81 Low
LH level 3.39 7.83, 1.05 .13 94 <.00001 Random inverse variance 3 169 Very low
LH/FSH ratio 0.61 1.42, 0.20 .14 79 .009 Random inverse variance 3 169 Very low
Testosterone 0.69 1.87, 0.50 .25 99 <.00001 Random inverse variance 2 88 Very low
Fasting insulin level 3.43 6.25, 0.61 .02 ––Random inverse variance 1 40 Low
Pregnancy rate 2.08 0.60, 7.19 .25 0 .44 Random inverse variance 2 191 Low
Acupuncture versus no treatment
Ovulation rate 0.35 0.14, 0.56 .0009 ––Random inverse variance 1 28 Low
Monthly menstruation rate 0.50 0.32, 0.68 <.00001 ––Random inverse variance 1 59 Low
LH level 0.53 1.46, 2.53 .60 60 .16 Random inverse variance 2 72 Very low
LH/FSH ratio 0.17 0.49, 0.15 .30 0 .48 Random inverse variance 2 72 Low
Testosterone 0.23 0.28, 0.18 <.00001 0 .38 Random inverse variance 2 72 Low
Fasting insulin level 1.31 0.78, 3.40 0.22 ––Random inverse variance 1 28 Low
Acupuncture versus medication
Monthly menstruation rate 0.14 0.05, 0.23 .003 ––Random inverse variance 1 86 Low
LH level 0.14 0.89, 0.60 .71 81 0.0003 Random inverse variance 5 327 Very low
LH/FSH ratio 0.10 0.23, 0.03 .15 0 .78 Random inverse variance 5 324 Low
Testosterone 0.04 0.11, 0.03 .30 93 <.00001 Random inverse variance 6 385 Very low
Fasting insulin level 0.10 1.14, 0.94 .85 0 .77 Random inverse variance 2 206 Low
Pregnancy rate 1.18 0.63, 2.20 .60 ––Random inverse variance 1 60 Low
Acupuncture with medication versus sham acupuncture with medication
LH level 1.82 3.44, 0.21 .03 94 <.00001 Random inverse variance 3 314 Very low
LH/FSH ratio 0.17 0.24, 0.10 <.00001 0 .79 Random inverse variance 2 254 Very low
Testosterone 0.10 0.20, 0.00 .06 94 <.00001 Random inverse variance 3 314 Very low
Fasting insulin level 1.90 2.46, 1.34 <.00001 ––Random inverse variance 1 104 Low
Pregnancy rate 5.06 0.76, 33.77 .09 Random inverse variance 1 25 Low
Acupuncture with medication versus medication alone
LH level 1.40 2.54, 0.25 .02 91 <.00001 Random inverse variance 8 673 Very low
LH/FSH ratio 0.58 0.82, 0.35 <.00001 92 <.00001 Random inverse variance 8 700 Very low
Testosterone 0.20 0.31, 0.10 .0001 98 <.00001 Random inverse variance 11 870 Very low
Fasting insulin level 2.50 2.77, 2.24 <.00001 0 .58 Random inverse variance 5 531 Low
Pregnancy rate 1.99 1.38, 2.87 .0002 0 .79 Random inverse variance 6 376 Low
CI =confidence interval, FSH =follicular stimulating hormone, LH =luteinizing hormone, MD =mean difference, RR =risk ratio.
Jo et al. Medicine (2017) 96:23 www.md-journal.com
7

affect hormonal levels such as LH, LH/FSH ratio, testosterone,
and fasting insulin. Neuroendocrinological mechanisms of
acupuncture have been extensively studied not only in pain
research
[49,50]
but also in reproductive medicine.
[51]
Acupuncture
is also known to modulate hypothalamic-pituitary-ovarian axis,
which can affect menstruation cycles.
[52]
Given that acupuncture
stimulates pituitary beta-endorphin production, which has a
tonic inhibitory effect on gonadotropin-releasing hormone pulse
generator and pituitary LH secretion, it is possible that
acupuncture may reduce ovulatory dysfunction and thus decrease
the secretion of ovarian androgens in women with PCOS.
[51]
Considering detected heterogeneity from our analysis, known
variability in hormonal levels, the poor standardization of assays,
and the specific PCOS phenotypic features,
[53,54]
however, the
currently available data from RCTs has yet to allow us to draw
any firm conclusion whether acupuncture affects hormonal
levels, thus recovering ovulatory function and menstruation cycle
in women with PCOS.
The pooled data showed that acupuncture significantly
increased pregnancy rates when added to medication compared
to medication alone. However, as the definition of pregnancy (ie,
clinical pregnancy determined by ultrasound) was not uniform
across studies, this finding needs to be confirmed in future trials
with clearly defined outcome measures.
Regarding safety, 11 of 27 studies reported adverse events such
as mild bleeding and pain at the site of needling, fatigue, dizziness,
and short-term nausea; however, it appears that these occur less
frequently when compared with the medication groups.
Additionally, 2 trials reported that when acupuncture was
added, it reduced adverse events associated with CC
[22]
or
metformin.
[20]
Future clinical trials should not neglect to report
adverse events associated with acupuncture clearly, including
frequency and severity.
[55]
4.3. Strengths and limitations of this review
We acknowledge that there are recently published systematic
reviews and meta-analyses.
[12–14]
However, they showed differ-
ences in their results and conclusions. The reasons for these
discrepancies may arise from the different search strategies, data
extraction, and analysis method. In particular, the Cochrane
review has been ignored various hormones related with PCOS.
[12]
We tried to include key reproductive outcomes associated with
PCOS as well as important clinical outcomes including ovulation
rate, pregnancy to judge the efficacy, and safety of acupuncture in
women with PCOS.
Consistent with other systematic reviews on acupuncture, a
big limitation of this report lies in the clinical and methodologi-
cal diversity of the included studies. PCOS itself is also
heterogeneous by nature in terms of clinical and biochemical
features. The PCOS phenotypic variability among participating
women may have created a variety of clinical manifesta-
tions.
[5,56]
The distribution of age, ethnicity, and BMI can
contribute to different manifestations of PCOS.
[56,57]
Also, some
studies adopted CHM as a control group which may not have
been standardized. All these clinical as well as methodological
diversities and complexities of PCOS may have yielded
considerable heterogeneity in our meta-analyses, making
generalizability more complicated. On the other hand, only 3
trials reported a formal sample size calculation, and it is of note
that most of the included trials are not entirely free from type II
error due to small sample sizes.
4.4. Implications for further studies
To confirm the ovarian activity, assessments should be conducted
more rigorously in future trials. In this review, only 2
studies
[10,44]
used elevated serum progesterone level >3 ng/mL
as indicative of ovulation. Anti-Müllerian hormone (AMH) is
positively correlated with the ovarian follicle pool, is elevated in
women with PCOS, and has been suggested as a diagnostic
tool.
[58,59]
AMH could be a useful parameter to assess the severity
of PCOS
[60]
and the impact of acupuncture in patients with
PCOS.
[58]
The collection of pre- and posttreatment blood samples
at nonstandardized times in the menstrual cycle could be a
confounding factor.
[5]
Moreover, outcome assessment in the
majority of trials occurred immediately following the interven-
tion period, and thus we are left with no information on how long
acupuncture’s effect may persist. More studies with long-term
follow-up are needed to examine the effectiveness of acupuncture
for improving live births and to assess the sustainability of effect.
Most of the included studies either inadequately reported or
did not clearly report methods related to important biases such as
randomization/allocation concealment and blinding methods.
Future trials should improve their reporting quality by following
the Consolidated Standards of Reporting Trials (CONSORT)
statement
[61]
and the Standards for Reporting Interventions in
Clinical Trials of Acupuncture (STRICTA).
[62]
There is an ongoing, large, multicenter RCT from mainland
China, Hong Kong, Sweden, and the United States to test the
effect of acupuncture with or without CC on live births in women
with PCOS.
[9]
The results of this RCT will add more solid
scientific evidence on the effectiveness and safety of acupuncture
for patients with PCOS.
5. Conclusion
This systematic review and meta-analysis suggests that the
evidence base for the use of acupuncture for improving ovulation
and menstruation rates and other hormonal changes in women
with PCOS is weak. Given the poor reporting and methodologi-
cal flaws of existing studies, large-scale, long-term RCTs with
rigorous methodological input are needed to clarify the role of
acupuncture in this population.
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