‘What is the evidence for the effectiveness of acupuncture in the treatment of Polycystic Ovary Syndrome (PCOS) in women of reproductive age?’ Anmerkung der Autorin: Diese Arbeit wurde im Rahmen des MSc Studiums am NCA erstellt. Auf Grund der Methodik fehlen die in der Praxis angewandten individuellen Behandlungen sowie ergänzende Techniken der TCM.

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PCOS und Akupunktur

‘What is the evidence for the effectiveness of acupuncture in the treatment of Polycystic Ovary Syndrome (PCOS) in women of reproductive age?’

Anmerkung der Autorin:

Diese Arbeit wurde im Rahmen des MSc Studiums am NCA erstellt. Auf Grund der Methodik fehlen die in der Praxis angewandten individuellen Behandlungen sowie ergänzende Techniken der TCM.

Des weiteren erhebt diese Arbeit keinen Anspruch auf Vollständigkeit und stellt kein Heilungsversprechen dar.

1. Introduction

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder, related to irregular menstruation and increased androgenic hormones (El Hayek et al., 2016). According to the ‘International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018’ (Misso et al., 2018) its incidence is in 8-13% of women in reproductive age. Furthermore, this guideline describes psychological, reproductive and metabolic features for PCOS.

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1.1 Diagnostic criteria

One common problem in the research of PCOS is the use of different definitions, due to a variety of phenotypes (Balen and Michelmore, 2002). The lack of a uniform definition is also from clinical significance. Depending on the speciality of the doctor, the diagnosis will be made. For instance, a gynaecologist might be more interested in the reproductive aspects of PCOS, while an endocrinologist concentrates on impaired glucose tolerance (IGT). Hence, discrepancy in definition may lead to different treatments (Cussons et al., 2005).

Initially described as ‘amenorrhea associated with bilateral polycystic ovaries’ by Stein and Leventhal in 1935, the diagnostic criteria (DC) were changed and updated various times. Hyperandrogenism and chronic anovulation were  included among the DC since the first conference of PCOS supported by the ‘National Institute of Health’ (NIH) in April 1990 (Azziz, 2006).

Because of the variety of symptoms, in 2003 the ‘Rotterdam Consensus Workshop’ (ROT) revised these criteria (Rotterdam, 2004). The scientists decided to broaden the criteria and included polycystic ovaries, diagnosed via ultrasound. Following the ROT, two out of three symptoms should appear. Hence, hyperandrogenism is not a deciding factor anymore.

Azziz (2006) questioned these criteria because it did not correspond with his observations.

In 2009 Azziz et al. drafted guidelines with the ‘Androgen Excess-PCOS-Society’ (AE-PCOS). The society pointed out the difficulty of providing a definition for a syndrome with different phenotypes and no uniform aetiology. As opposed to ROT, the AE-PCOS considers hyperandrogenism as diagnostic factor.

Table 1: DC (Azziz, 2006, Azziz et al., 2009; Rotterdam, 2004)

NIH

1990

ROT

2003

AE-PCOS

2009

Hyperandrogenism

Hyperandrogenism

Hyperandrogenism

Chronic anovulation

polycystic ovaries

Ovarian Dysfunction

 

An- or Oligo-Ovulation

 

 

1.2 Treatment recommendations

Recommendations for the treatment of PCOS depend on the presenting features of the disease as well as the desired result (pregnancy, balanced androgens, etc.). E.g., people with obesity and IGT should modify their lifestyle first and then metformin can be recommended. Fertility issues should be treated primarily with clomiphene citrate (CC), while hyperandrogenism can be improved with oral contraceptives (Leon and Mayrin, 2018).

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1.3 Intervention: Acupuncture

 

The use of complementary and alternative medicine (CAM) in the British population is significant: a survey from Thomas and Coleman (2004) evaluated a 10 per cent use of CAM from British adults.

Traditional Chinese Medicine (TCM) as a medical system based on 2500 years of experience (Noll, 2010). Originally, acupuncture belonged to the field of TCM (Kaptchuk, 2002) and involves the insertion of a needle into the skin. Integration of acupuncture as a relatively safe treatment in conventional care is increasing (Witt et al., 2009), especially in gynaecology (Kang et al., 2011). Furthermore, a review by Franconi et al. (2011) provides evidence of the usefulness of acupuncture to treat  infertility due to PCOS.

Stimulation of the needle can be done manually or electrically with electro-acupuncture (EA). Johansson and Stener-Victorin (2013) have reported that an effect of acupuncture in PCOS is feasible because nervous pathways are activated.

1.4 Relevance for medicine

 

It is important to research PCOS, because the overhead costs for PCOS are tremendous and the quality of life of patients with PCOS is reduced (El Hayek, 2016). The associated morbidities, e.g. infertility, complications in pregnancy, IGT, cardiovascular disease, are huge in number and long-term (Fauser et al., 2012). With up to 70% undiagnosed women (Misso et al., 2018) and continuous amended guidelines, more information about PCOS is needed. Furthermore, only 2 systematic reviews (SRs) about acupuncture for PCOS are available via the COCHRANE Library. Both show limited evidence for the effectiveness of acupuncture in reproductive outcome (Jo et al., 2017) and ovulatory disorders (Lim et al., 2016).

 

Available SRs are commonly based on just one or two DCs (Jo, Lee and Lee, 2017; Luo et al., 2018). Recently, an SR was published by Jo, Lee and Lee (2017), only including Rotterdam criteria. Also, this SR evaluated research only until 2016. Due to the increasing importance of PCOS, a more up to date review would be appropriate. A broad search for the Medical Subheading (MeSh)-Term ‘ovarian syndrome, polycystic’ in PubMed, limited to 2017/01/01 – 2018/12/31 resulted in more than 1000 published papers (appendix 1).

1.5 Aims and objectives

 

In the context of the heterogeneity of the DC and the importance for actual research, this scoping review (ScR) aims to provide a broader and actual approach to evaluate the effectiveness of acupuncture for women suffering from PCOS. First, the quality of methodology will be assessed, second, the results will be presented in a narrative synthesis, and finally, a discussion about the findings and a conclusion with recommendations for further research will complete this review.

2. Methods

 

To answer the RQ in a suitable way, an ScR was conducted. ScRs evaluate the existing literature in a field of interest (Peters et al., 2015). The broader approach of an ScR compared to an SR (Malley, Arksey and O’Malle, 2005) is especially suitable for the different DC. In general ScRs do not concentrate on a stated RQ, nor do they assess the quality (Malley, Arksey and O’Malle, 2005). But the use of ScRs is rising, despite there being neither an existing definition nor a standardized process (Pham et al., 2014). Therefore, this review provides a broader definition of the DC and a less extensive search, while critically appraising the included studies.

 

2.1 Search strategy

 

As first step a limited search has been conducted. Three relevant databases addressing the clinical management have been selected:

 

  1. PubMed

PubMed is a freely-available database, providing a comprehensive overview about Medical Subheadings (MeSH)- and PCOS-related terms. Also, PubMed is generally accepted as an important database for biomedical literature (Madhavan ,n.d.) and is most often used by medical professionals (Greenhalgh, 2014); it is an appropriate database for an RQ in the medical field.

 

  1. Cochrane

The Cochrane Library is a freely-available collection of databases, covering

a wide range for the research of healthcare treatments (Chapman, 2009). The importance of the Cochrane Collaboration for CAM is increasing. Therefore, a topic list with categorizations of CAM has been developed for Cochrane reviews (Wieland, Manheimer and Berman, 2011).

 

  1. AMED

The  Allied and Complementary Medicine Database (AMED) is a database which is providing a classification of articles related to medicine into broad sub-groups, e.g. acupuncture or homeopathy. The aim of  AMED is to covers information, which is not provided by other databases (Roberts, 1995). ). For instance, a comprehensive SR from 2018 does not include AMED (Luo et al., 2018). Furthermore, the relevance of AMED for CAM is significant (Boehm et al., 2010

Through the Northern College of Acupuncture (NCA), access is available.

 

Multiple synonyms for PCOS have been used to search in the ‘title/ abstract’ field. Synonyms were identified through MeSH- terms, manual research in books and articles and discussions with experts. For instance, the disease is also referred as hyperandrogenic anovulation due to the symptoms associated with PCOS, also known as Stein-Leventhal-Syndrome.

 

In addition, MeSH-terms for a broader search have been implemented.

Finally, a time limitation for publishing was set for the 1st of April 1990, because of

the first NHI-sponsored conference for PCOS.

The full details of the search strategy are provided in appendix 1.

 

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2.2 Study selection

To provide a framework, the PICO(S) (Population, Intervention, Comparator, Outcome, Study design) method was applied (table 2). PICO helps to concentrate on the research question and to be precise (Schardt et al., 2007). Designed for clinical studies, the PICO-Approach provides a step-by-step guide to limit the scope of a review (Springett and Campbell, 2006).

 

2.2.1 Population of interest

The population of interest consists of women in reproductive age, defined from the World Health Organisation (WHO) to be within 15-49 years of age. The menstruation cycle of teenage girls is variable and often prolonged (Hillard, 2016). Therefore, adolescents are excluded.

To provide extensive results, the ScR will include the DC of Rotterdam, NIH and AE-PCOS.

Studies, including other aetiologies of hyperandrogenism e.g. hypothyroidism or Cushing-syndrome are excluded.

2.2.1 Intervention

The intervention focused on in this ScR included acupuncture and its variations, such as EA and laser acupuncture (LA, Biomodulation).

EA was implemented in the search strategy as recommended by recognized authorities in the field of TCM (Lyttleton, 2013). Laser acupuncture is increasingly used to treat infertility (Abdel-Salam and Harith, 2015) and has already been analysed in some recent studies (El-Shamy, EL-Kholy and El-Rhaman, 2018).

Since there is little published on acupuncture as the only treatment for PCOS and the first line treatment for ovulation induction is CC (NICE, 2013), the combination of acupuncture and CC is included in this survey.

The use of TCM implies using Chinese herbs. Due to the individual nature of herbal prescriptions, an evaluation is very difficult and herbal medicine treatments are excluded in this ScR.

All other interventions e.g. changes in lifestyle are excluded, to concentrate more on the effectiveness of acupuncture.

2.2.3 Comparison

Reporting on acupuncture in research is complicated due to different styles or number of treatment sessions (MacPherson et al., 2010). The body might response different depending on various factors e.g., intensity and duration of stimulation.

For this reason, more comparators will be considered:

  1. Control-acupuncture: acupuncture-like placebo method
  2. Medication
  3. No treatment

2.2.4 Outcome

PCOS is a set of symptoms, ranging from menstrual disorders to long-term metabolic or cardiovascular complications, to name a few (Broekmans et al., 2006). The WHO categorized PCOS as a group II ovulation disorder (NICE, 2013). Furthermore, the most frequent reason for anovulatory infertility is PCOS (Koivunen et al., 2008). For that reason, this review concentrates on improvement of ovulation as outcome.

An appropriate measurement to measure ovulation is serum progesterone in the mid-luteal-phase, depending on the length of the individual cycle (Misso et al., 2018, NICE 2013). The basal body temperature is not reliable (NICE, 2013) and is excluded, as well as measurement of the luteinizing hormone (LH) peak, since PCOS often implies an excess of LH due to the pathophysiology (Rotterdam, 2004; Kumar and Sait, 2011).

2.2.5 Study design

Quantitative research with experimental study design is an appropriate method to test the effect of an intervention (Shadish, Cook and Campbell, 2002) and to find out about causality between two actions (Celano, 2014).

Moreover, randomized controlled trails (RCTs) are the gold-standard for health research (Jadad, 2004).

Given that acupuncture is a part of CAM in all its complexity, rigorous RCTs are difficult to assess (Baxter et al., 2008) and quasi-experimental studies are therefore also included in this ScR.

 

Table 2: PICOS

Population of interest

 

Women in reproductive age diagnosed with PCOS

Intervention

 

Acupuncture

EA

LA

Comparator

 

Control-acupuncture

Standard care

No treatment

Outcomes of interest

Improvement of ovulation, measured with serum progesterone level

Study design

RCT, quasi-experimental studies

2.3 Plan for data extraction

A summary of study design, study duration, outcome, number and age of participants, DC, intervention, comparator and results is provided in a Study Characteristic Table. This table outlines an overview about the final studies. Furthermore, this table is the basis for an appropriate data analysis.

2.4 Critical Appraisal

To assess the methodological quality, the final studies were critically appraised, depending on their study design:

To ensure that the effect of randomized trials is not over- or underestimated because of existing bias, the Cochrane Collaboration developed a tool (Higgins et al., 2011): for all RCTs the “Revised Cochrane Risk Of Bias tool for randomized trials” (RoB 2) will be used to assess trial quality (Higgins et al., 2018). Based on empirical evidence and theoretical considerations the authors developed a framework. They organised data into 5 domains as follows: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result.

An appropriate tool to assess the methodological quality for SRs is the Risk of Bias in Systematic Review (ROBIS) (Whiting et al., 2016). This recently developed tool should address the internal validity and appraise the risk of bias (Gates et al., 2018).

Finally, the results will be summarized in a risk of bias Quality Appraisal Table.

 

2.5 Plan for narrative synthesis

Because of the variety of presentation of PCOS, a meta-analysis or statistical data-analysis is not appropriate. For synthesising the collected results, a narrative analysis is preferable (Ryan, 2013).

The heterogeneity of the included papers will be synthesised. Distinctions due to different study designs or interventions should be examined for their potential influence on the results (Ryan, 2013).

Features regarding different definitions of PCOS should be examined, e.g. restrictions for age in the population. Another characteristic of interest is the influence of obesity, which is a high risk for anovulation (Fauser et al., 2012). For that reason, the Body Mass Index (BMI) should be included in the synthesis.

3.RESULTS

3.1 Data collection

The search was conducted first via Cochrane on the 22th of December 2018 with 100 trials as result. Further 10 articles were achieved in the same day through AMED. PubMed was searched on the 23th of December 2018 and resulted in 185 records. 295 records were stored electronically in the Mendeley reference manager (Mendeley Database, 2019) and 57 duplicates removed.

 

238 titles and abstracts were screened for including the PICOS-criteria (table 2). 197 Studies not fitting the eligibility criteria were excluded. For 38 studies the full-texts were accessed, however for 3 articles, full texts were not available via Google scholar, the college librarian, Science Direct or other free sources.

 

10 duplicates and 4 papers with outcomes other than ovulation, 6 with other measurements than progesterone level, and 3 not-RCTs have been excluded. One article did not meet the eligibility criteria because of animal testing and a further 11 papers could not be included in the analysis due to language restrictions.

 

Finally, 2 papers were critically appraised and synthesized.

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009) presents an overview of the conducted search in figure 1 (provided by the author).

 

From each study, the study design, number and age of participants, DC, intervention, comparator and results were extracted and summarized in table 2.

 

#1) Wu et al. (2017):

The study duration of this 2 x 2 factorial RCT was 28 month with 1000 women in the age of 18-38 and the primary outcome of live birth. Due to the RQ, this data extraction will concentrate on the secondary outcome of ovulation. Wu et al. (2017) used modified ROT as DC, instead of an- or oligoovulation they chose an- or oligomenorrhea. The researcher provided 2 interventions (acupuncture and CC) and compared them with two control mechanism (control-acupuncture and placebo). The results show improvement of ovulation in the CC-groups compared to placebo, but no significant difference between acupuncture and control acupuncture.

#2) Jo et al. (2017)

This SR searched in 15 databases (international, Chinese, Korean and Japanese) for the primary outcome ovulation until February 2016. Finally, 2093 participants without a limitation of age and matching the DC of ROT were evaluated, but only 2 RCTs reported ovulation rate as outcome. However, the results of this SR show a low level of evidence of improvement of ovulation with acupuncture. The mean difference (MD) of acupuncture compared to sham-acupuncture was – 0,03 and compared to no treatment 0,35.

To provide more information, the data of both included trials were extracted separately:

#2a) Johansson et al. (2013)

For this trial, 32 women with PCOS, diagnosed with ROT in the age of 18-38 years were recruited and data from 15 month evaluated. The effectiveness of acupuncture was examined with an attention control group as comparator: participants met a therapist, but instead of a treatment they listened to relaxing music. The finding of 0,76:0,41confirmed a higher rate of ovulation with acupuncture.

#2b) Pastore et al. (2011)

The researcher explore the primary outcome ovulation of 96 participants in the age of 18-43 for a duration of 45 month. All of them were diagnosed for PCOS using the AE-PCOS criteria. The frequency of ovulation did not differ significantly between acupuncture and sham-acupuncture with 0,37 to 0,4.

In addition, a Data Extraction Table for each paper with more details is provided in appendix 4.

 

 Table 3: Study characteristic table

Source

Methods

Outcome

Participants

Intervention

Comparator

Results

Study-ID

Author/ title/ year

Study design

Study duration

 

Num-ber

DC

Age

   

#1

Wu et. al (2017)

 ‘Acupuncture and clomiphene for infertility in the polycystic ovary syndrome: a multicentre rondomized controlled trial’

RCT

28 month

Primary:

Live birth

Secondary:

Ovulation

1000

Modified Rotterdam

18-38

Acupuncture + CC

Control-acupuncture + CC

(94.0):(92.4)

Acupuncture + placebo

Control-acupuncture + placebo

(70.0) :(69.8)

no significant difference between acupuncture and control acupuncture

#2

Jo et al. (2017)

‘ Acupuncture for polycystic ovarian syndrome: A systematic review and meta-analysis’

SR

Until February 2016

Primary:

Ovulation

2093

Rotterdam

No defi-ntion

Acupuncture

Sham-acupuncture

 MD:

– 0,03

no treatment

MD: 0,35

medication

No information

(NI)

Acupuncture + medication

Sham-acupuncture + medication

NI

 

medication alone

NI

Low level of evidence of improvement of ovulation with acupuncture

#2a)

Johansson et al. (2013)

‘Acupuncture for ovulation induction in polycystic ovary syndrome: a randomized controlled trial’

RCT, included in 2

15 month

Primary:

Ovulation

32

Rotterdam

18-38

Acupuncture

No treatment, attention control

0,76:0,41

Higher ovulation frequency with acupuncture

#2b)

Pastore et al. (2011)

‘True and Sham Acupuncture Produced Similar Frequency of Ovulation and Improved LH to FSH Ratios in Women with Polycystic Ovary Syndrome’

RCT, included in 2

45 month

Primary:

Ovulation

96

AE-PCOS

18-43

Acupuncture

Sham-acupuncture

0,37:0,4

        

Ovulation rate did not differ between groups

3.2 Methods of quality control

To decide whether scientific research is important for the reader´s field of interest, selecting and appraising is necessary (Salomon and Young, 2009).

Hence, to rate the methodological quality, a formal assessment of each paper was conducted. All details are provided in the Quality Appraisal Table in appendix 3.

The risk of bias in RCTs, the RoB 2 (Higgens et al., 2018) was used for Wu et al. (2017):

First, some concerns arose in domain 1 for the randomization process: the acupuncturists were not blinded. On the other hand, due to this intervention, blinding might not be feasible (Ernst, 1991) and no deviations would be expected.

Second, the trial was not analysed in the way, the previous published protocol (clinicaltrials.gov: NCT01573858) described. The rationale for this change in the statistical analysis approach is to focus on main effects and interaction rather than testing two acupuncture protocols. Further explanations and justifications from the authors are published in various articles (Stener-Victorin, 2017; Ma et al., 2018). However, some concerns for the risk of bias in selection of the reported result remain.

The SR of Jo et al. (2017) was assessed for the risk of bias with ROBIS:

First of all, the definition of population is lacking a restriction for the age. Considering the RQ and discussions about the definition of PCOS, a definition of the age of included participants might matter. For instance, Azziz (2006) questioned the Rotterdam-DC and urged for a proper definition of the age range.

For this reason the eligibility criteria might not be appropriate for the RQ. However, both trials with the outcome of interest ‘ovulation’ (Johansson et al., 2013; Pastore et al., 2011) included in this SR do include only women older than 18 years.

The SR’s authors appraised included articles with the ‘Cochrane Collaboration’s tool for assessing risk of bias in randomised trials’ (2011).

Some questions occurred here, because of discrepancies between the summary of risk of bias and the author’s judgement in the appendix: Figure 2 in the main body presents different results than appendix S3.

However, assuming that this is rather a methodological mistake than a bias, the SR presents a low risk of bias.

3.3 Narrative synthesis

One RCT (Wu et al., 2017) and one SR (Jo et al., 2017) have been evaluated to answer the RQ. The SR provides two RCTs (Johansson et al., 2013; Pastore et al., 2011) meeting the inclusion criteria. For a better comparison, this synthesis will concentrate on the three RCTs and just briefly describe the SR. A comprehensive table for the data synthesis is provided in appendix 4.

3.3.1 Participants

The largest trial by far was conducted by Wu et al. (2017) with 1000 women, while Pastore et al. (2013) and Johansson et al. (2013) dealt with smaller samples (96,32).

Pastore et al. (2011) are the only authors with more restrictions for the DC. They limited the DC to the appearance of oligomenorrhoe and hyperandrogenism as determined in the AE-PCOS. Both other articles as well as the SR diagnosed PCOS used the broader Rotterdam criteria.

All evaluated RCTs have a required age from 18 years, only Jo et al. (2017) is missing age details. However, Pastore et al. (2011) set the maximum age at 43 years, which still meets the WHO criteria for reproductive age and with that of the RQ. Johansson et al. (2013) and Wu et al. (2017) limited the age to 38 years. None of the papers gave a rationale for this decision, implying some weakness on this point.

While every final paper employs the BMI as part of the population criteria, how this measurement was assessed was totally different:

  • Equal distribution
  • Pastore et al. (2011) concentrated on avoiding risk of bias because of baseline-difference for weight

2)        Limitation

  • Johansson et al. (2013) excluded BMI > 30. They describe the possible effect of intervention on the weight, but provided no data about the allocation of the BMI.
  • Detailed information
  • Only the trial from Wu et al. (2017) separated the results for 176 obese women with a BMI > 28, which is a strength of this study.

3.3.2 Intervention

In accordance with the RQ, the intervention chosen was acupuncture in one RCT (Wu et al., 2017), and in the overriding SR (Jo et al., 2017) acupuncture was combined with medications. The administration of the treatment was very similar for Wu et al. (2017) and Johansson et al. (2013):

  • Twice per week
  • Two alternating acupuncture protocols

 

Pastore et al. (2011) reduced treatment to once per week after 4 weeks, based on one acupuncture protocol with the smallest number of 12 sessions. The largest trial (Wu et al, 2017) presented the highest number of treatments, 32, which is similar to Johansson et al. (2013) with 20-26 sessions.

The needle-manipulation was similar in all articles.

Detailed information about the intervention executor (e.g. education and experience) was missing.

 

3.3.3 Comparator

The control mechanism points out discrepancies between the research papers:

 

  • Control acupuncture
  • Instead of active acupuncture, the needle in the Wu et al. (2017) trial was only inserted superficially and without manipulation in non-acupuncture points (AP)
  • Park-Sham-Device (PSD)
  • The PSD was developed to perform undistinguishable but inactive acupuncture (Park et al., 2002). Pastore et al. (2011) used this non-penetrating method along with avoiding real APs.
  • No treatment
  • Only Johansson et al. (2013) is compared acupuncture to a control group. The control participants attended the same number of sessions, and just listened to music and relaxed.

 

3.3.4 Results

 

Only Johansson et al. (2013) supported the effectiveness of acupuncture for ovulation in PCOS with a significantly higher ovulation rate in the acupuncture group (0,76:0,41). Both trials, imitating acupuncture as control mechanism (Wu et al., 2017; Pastore et al.,2011), found no difference between the groups. Therefore, the effect of control-acupuncture should be considered in the discussion.


4. Discussion

 

4.1 Summary of main findings

The ScR showed that overall the evaluated articles did not support the effectiveness of acupuncture for PCOS with the specific outcome of ovulation.

After identifying almost 300 records, only 41 remained with access to the full text and just two final papers matched the PICOS criteria left over, one RCT (Wu et al., 2017) and one SR (Jo et al., 2017). Despite searching the SR using ovulation as primary outcome, of the1197 records identified at the beginning of the search, only two papers (Johansson et al., 2013; Pastore et al., 2011) reported ovulation rate. Furthermore, the in the search strategy included laser acupuncture presented no results.This leads to the assumption that appropriate research in this field is lacking.

The two papers presented in this review are Wu et al. (2017), refuting significant differences in the acupuncture group, and Jo, Lee and Lee (2017), which includes two RCTs: Johansson et al. (2013), supporting the RQ, and Pastore et al. (2011), who contests the effectiveness of acupuncture in PCOS.

It is notable that the supporting RCT (Johansson et al., 2013) shows a very significant difference with 35% more ovulations in the acupuncture group. Comparing the trials included in this review, only Johansson et al. (2013) compares the intervention with an attention control group: participants met a therapist and had a session in the same way provided for the acupuncture group. No intervention was performed here except of listening to music. In this case, the control mechanism is not active and can be interpreted as no treatment. Since this is a significant difference compared to the other papers included in this ScR, the impact of the comparator should be deeper analysed:

The effect of penetrating the skin on non-acupuncture points (APs) is unclear and might lead to physical effects similar to acupuncture (Streitberger and Kleinhenz, 1998). In addition, Li et al. (2013) reviewed the effect of acupuncture on central autonomic regulation. They confirmed evidence for changes in brain regions and modulation of neurotransmitters, but could not differentiate between the effects of different APs.

Moreover, one of the researchers of the Wu et al. trial (2017) published a narrative review contradicting their own findings and supporting the role of acupuncture for ovulation induction compared to no treatment (Stener-Victorin, 2017). Yongming Li (2017) explained in an article published in the Journal of the American Medicine Association (JAMA) that control acupuncture is actually an active treatment and not a control mechanism. Therefore, he questioned the findings of Wu et al. (2017).

Pastore et al. (2013) compared acupuncture with sham- acupuncture. This discussion about appropriate comparators to evaluate the effectiveness of acupuncture has existed for over 30 years, but is still relevant. In his essay from 1998, Hammerschlag addressed this issue in clinical trials (Hammerschlag, 1998). A new Japanese study about acupuncture sensation has explored the placebo effect (Takayama et al., 2018). The Japanese scientists observed different effects between penetrating and needles just touching the skin. Recently, a ‘Guideline for Randomized Controlled Trials of Acupuncture’ has been published in the ‘ American Journal for Chinese Medicine’ (Chen et al., 2019), investigating appropriate control mechanisms for acupuncture.

Previous articles (Johansson and Stener-Victorin, 2013) underpin the hypothesis of the RQ. Also, a recent published SR (Luo et al., 2018) reports 80% effectiveness of acupuncture for PCOS in all included studies.

Today, the presence of at least two Rotterdam criteria is widely accepted for diagnosis of PCOS (Leon and Mayrin, 2018), but the inconsistency of the DC as well as the need for more markers, e.g. identification of PCOS-genes or hormonal testing, challenges evidence-based analysis (Azziz et al., 2009). The findings of this review confirmed this challenge: one RCT (Wu et al., 2017) was built up on ‘modified ROT’. The authors have replaced an- or oligo-ovulation with an- or oligomenorrhoea.

As mentioned above, Jo, Lee and Lee (2017) included a trial ( Pastore et al., 2011) diagnosed with AE-PCOS despite their stipulation that they would follow the ROT. This is not consistent with the statement of the SR to use ROT as DC.

 

4.2 Methodological strengths and limitations of included trials

 

Wu et al. (2017) is a very recent trial with a large sample size (1000 participants). Furthermore, the 2 x 2 factorial trial provides comprehensive findings about the effect and interactions between acupuncture and medication (CC). By adding another arm for ‘no treatment’, the RCT would have been even more appropriate to test acupuncture (MacPherson et al., 2008). Also, this would reduce the possibility of achieving similar effects from acupuncture and control-acupuncture, as described by Li (2017). However, Wu et al. (2017) recognised this as a limitation of their trial and that the possibility of a placebo effect exists.

Luo et al. (2018) pointed out a lack of good quality in research regarding effectiveness of acupuncture for PCOS. The findings of this ScR present weak quality in few points:

Wu et al. (2017) revised their statistical analysis approach. The deviation from the protocol challenges the quality of the results (Kuang et al., 2018). However, a published article explained the reasons for the change (Ma et al., 2018). Jo, Lee and Lee (2017) published a questionable risk of bias figure in the main body. This leads to confusion for assessing the results.

Furthermore, Szmelskyj and Szmelskyj (2017) published an article, questioning the use of electro-acupuncture: low-frequency, as used by Wu et al. (2017), seems to lead to an increase of ovarian blood flow. According to the authors of the article, more than 15 studies have already confirmed that the ovarian blood flow in PCOS patients is excessive. They conclude that the results might have been influenced because of increasing the blood flow.

Wu et al. (2017) are the only authors who considered the possibility of different outcomes for patients with a higher BMI. Awareness to the rising importance of BMI and obesity often associated with PCOS (Broekmans et al., 2006), is a strength of the RCT of Wu et al. (2017). Misso et al. (2018) provided one section in the guidelines for PCOS for patients with obesity. Ethical issues may asked for the appropriate treatment for obese patients in a trial. If most participants in the RCT (Wu et al., 2017) are obese, the intervention should also add physical training as the first line treatment for PCOS with obesity (Zhang et al., 2018).

However, Johansson et al. (2013) and Pastore et al. (2011) did not pay a lot attention to the BMI.

 

4.2.1 Acupuncture in research

All evaluated papers were limited by the fixed acupuncture protocol and western medicine diagnoses.

Research in acupuncture is still a challenge and concerns in acupuncture studies should be explained. Acupuncture is an integrated part of TCM (Maciocia, 2015). In general, TCM is very individual in treatment and diagnosis (Ernst, 1994).

The complex concept of TCM is based on dynamic processes (MacPherson et al., 2017). Moreover, from the perspective of TCM, one pattern can produce different manifestations (Lewis, 2004). Therefore, the approach of TCM in contrast with western medicine is totally different. Several authors point out this problem and have developed concepts for future research (Hammerschlag, 1998; Kaptchuk, 2011; Langevin et al., 2011; MacPherson et al., 2008, 2010).

Also, the treatment in Chinese medicine consists of different techniques. Beside acupuncture, for example herbal medicine or tuina-massage is part of TCM. For this reason, a TCM practitioner chooses the method of treatment regarding to the diagnosis. For instance, the combination of acupuncture and moxibustion is an important component of TCM (Yongqiang and Chen, 1993). For this reason, the use of a single method out of a whole system is questioned.

The evaluated papers are all using acupuncture protocols. The Guidelines and Guidance Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRISTA) (MacPherson et al., 2010) are recommending the use of acupucnture protocols to provide a uniform treatment. Again, this standardisation is contradicting the principles of TCM.

4.3 Limitations of this ScR

As discussed in the introduction, measuring ovulation in PCOS is difficult. To be as accurate as possible, this ScR chose the level of progesterone as an indication of ovulation. During the literature search, more studies with other measurements appeared, implying that more than one method should have increased the results. 6 studies were excluded, even though ovulation was the outcome, because of not using progesterone levels as measurement.

Another limitation and maybe the most important restriction is the language: for this reason 11 articles were excluded.

A possible limitation is the use of only 3 databases, all settled in Europe. Due to the history of acupuncture, research in China is very common and Chinese databases could cover more papers. However, since Jo, Lee and Lee (2017) have also been searching in Chinese, Korean and Japanese databases, without providing much more results in the end, this restriction is not strong.

First line treatments for PCOS are changes in lifestyle, but the review includes only intervention of acupuncture and combinations with CC. Like in the trial of Wu et al. (2017), this may lead to misinterpretation.

A few articles could not be accessed in full. The authors of these missing texts have been contacted, but they have not yet replied.

4.4 Conclusion and future research

The lack of evidence for the effectiveness of acupuncture in ovulation induction for women with PCOS may be because of the various challenges implementing an old medical system in modern research. Furthermore, the different phenotypes of PCOS provide a variety of symptoms, which leads to heterogeneity in published RCTs and SRs. If the whole concept of TCM and acupuncture would be applied, different findings are expected. Particular the combination of acupuncture and herbal medicine has positive effects in PCOS-patients (Yu et al., 2013). For instance, a Chinese RCT with combination of acupuncture, herbal medicine and CC showed increasing pregnancy rates (Jiang et al., 2015).

One benefit of TCM is the use of pattern diagnosis: Instead of treating the symptoms, TCM discovers the imbalance that is causing the symptom. Deficiency or excess of energetic systems in the body are balanced to achieve overall health (Lewis, 2004). This whole-body-system-medicine allows for individual treatment (Ried and Stuart, 2011). Particularly, for a disease with different phenotypes as presented in PCOS, this approach can be very useful. Kandace Cahill (2016) explained this concept by transmitting western phenotypes into TCM syndromes. To benefit more from the TCM diagnostic, studies should apply the syndrome differentiation used in TCM. Some reviews, evaluating the efficacy of Chinese herbal medicine, have already done this in an appropriate way. (Ried and Stuart, 2011; Zheng et al., 2015).

 

Implementing acupuncture in the context of TCM in clinical trials and gathering more knowledge about PCOS would greatly improve future research.

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