针刺治疗多囊卵巢综合征随机对照试验指南

Acupuncture for treating polycystic ovary syndrome: guidance for future randomized controlled trials 针刺治疗多囊卵巢综合征随机对照试验指南 1 first-author 2 3 4 5 1 1 3 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:qufan43@outlook.com †E-mail:qufan43@outlook.com Fan QU, MD, PhD, Fellow in the Research Council for Complementary Medicine (FRCCM), an editorial board member of Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), is an Associate Professor and PhD Supervisor at the Women′ s Hospital, School of Medicine, Zhejiang Uni-versity, China. As a Principal Investigator (PI), he has been awarded more than 10 grants in the last five years, published over 50 peer-reviewed papers and has filed 10 patents. In 2015, he was awarded the “Excellence in Integrative Medicine Research Award” by the European Society of Integrative Medicine. Dr. QU was a Work Package 10 (WP10) member in the Good Practice in Traditional Chinese Medicine (GP-TCM) Research in the Post-Genomic Era, a Coordination Action funded by the European Union′ s 7th Framework Program, and is now Co-Chair of the Pharmacology and Toxicology Interest Group, Good Practice in Traditional Chinese Medicine Research Association, European Union and he also serves as Vice-President of the Acupuncture Research Committee, Zhejiang Acupuncture Association, China. http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23559445&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23559459&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23559454&type= Fan QU, MD, PhD, Fellow in the Research Council for Complementary Medicine (FRCCM), an editorial board member of Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) , is an Associate Professor and PhD Supervisor at the Women′ s Hospital, School of Medicine, Zhejiang Uni-versity, China. As a Principal Investigator (PI), he has been awarded more than 10 grants in the last five years, published over 50 peer-reviewed papers and has filed 10 patents. In 2015, he was awarded the “Excellence in Integrative Medicine Research Award” by the European Society of Integrative Medicine. Dr. QU was a Work Package 10 (WP10) member in the Good Practice in Traditional Chinese Medicine (GP-TCM) Research in the Post-Genomic Era, a Coordination Action funded by the European Union′ s 7th Framework Program, and is now Co-Chair of the Pharmacology and Toxicology Interest Group, Good Practice in Traditional Chinese Medicine Research Association, European Union and he also serves as Vice-President of the Acupuncture Research Committee, Zhejiang Acupuncture Association, China. qufan43@outlook.com Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China School of Health and Social Care, London South Bank University, London, SE1 0AA, UK School of Health and Social Care, London South Bank University, London, SE1 0AA, UK Institute for Women’s Health, University College London Medical School, London, NW3 2PF, UK Institute for Women’s Health, University College London Medical School, London, NW3 2PF, UK UCLA Center for East-West Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Westlake Village, CA 91361, USA UCLA Center for East-West Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Westlake Village, CA 91361, USA College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China Objective: 2 To provide guidance for future randomized controlled trials (RCTs) based on a review concerning acupuncture for treating polycystic ovary syndrome (PCOS). Methods: 2 A comprehensive literature search was conducted in October 2015 using MEDLINE, EMBASE, SCISEARCH, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Menstrual Disorders and Subfertility Group trials register, Allied and Complementary Medicine (AMED), China National Knowledge Infrastructure (CNKI), and the Wanfang databases. RCTs comparing either acupuncture with no/sham/pharmacological intervention or a combination of acupuncture and conventional therapy with conventional therapy in the treatment of PCOS were included in this review. A quality evaluation was performed for each of the included studies. Results: 2 Thirty-one RCTs were included in the review and were divided into four categories according to the type of intervention used in the comparator or control group. Menstrual frequency, hormones, anthropometrics, insulin sensitivity, blood lipids, and fertility were used as the main measurements to assess the effects of acupuncture on the patients with PCOS. Thirty trials, except for one, showed an improvement in at least one of the indicators of PCOS after acupuncture treatment. However, normalizing the methodological and reporting format remains an issue. Conclusions: 2 Based upon this review of current clinical trials concerning acupuncture for treating PCOS, we provide guidelines for better clinical trial design in the future. 目的 2 基于对针刺治疗多囊卵巢综合征随机对照临床试验现状的系统总结和分析，提出对未来相关临床研究的建议。 创新点 2 首次对目前针刺治疗多囊卵巢综合征随机对照临床试验进行了全面的总结和分析，从研究设计和报告规范等方面提出了一系列改进的建议。 方法 2 对MEDLINE、EMBASE、万方和知网等八个数据库进行了针刺治疗多囊卵巢综合征相关文献的全面检索，按照纳入标准将文章进行分类和总结，并对每项研究进行了详细的质量评估。根据当前的研究情况对未来针刺治疗多囊卵巢综合征的随机对照临床试验提出了一系列建议。 结论 2 从如何完善实验设计，提高研究质量，加强报告规范等方面提出了一系列改进的建议，对未来针刺治疗多囊卵巢综合征随机对照试验的设计和实施提供了指导和帮助。 Acupuncture Polycystic ovary syndrome Randomized controlled trial 针刺 多囊卵巢综合征 随机对照试验 Introduction 1 Polycystic ovary syndrome (PCOS), a complex genetic disorder, is a significant women’s health issue, which shows an increasing annual prevalence (Franks, 1995 1995 ; Ehrmann, 2005 2005 ; Stefanaki et al., 2015 2015 ). It is characterized by the presence of polycystic ovaries, chronic oligo/anovulation, hyperandrogenism, infertility, hyperinsulinemia, insulin resistance, and obesity (Norman et al., 2007 2007 ). Patients with PCOS often need pharmacological treatment for a long period of time. First-line therapy for PCOS is oral contraceptives, which can effectively alleviate hirsutism and acne; however, these may adversely affect glucose tolerance, coagulability, and fertility (Lanham et al., 2006 2006 ). Acupuncture has been used to treat gynecological disorders for thousands of years (Zhou and Qu, 2009 2009 ). It is sometimes chosen by women with PCOS as an alternative therapy or used as an adjunct while undergoing infertility treatment (Stener-Victorin et al., 2008 2008 ). Previous studies have shown that acupuncture can effectively treat PCOS by: (1) modulating the sympathetic outflow through spinal reflexes; (2) affecting the hypothalamic pituitary adrenocortical (HPA) and hypothalamic pituitary ovarian (HPO) axes by increasing central β-endorphin (Johansson and Stener-Victorin, 2013 2013 ). Over 50 studies have been conducted to explore the effects of acupuncture on PCOS (Stener-Victorin et al., 2008 2008 ; Zheng et al., 2012 2012 ). The aim of this review is to provide guidance to augment the accuracy of future randomized controlled trials (RCTs) relating to acupuncture for treating PCOS. Methods 1 A review of the existing RCTs on acupuncture for the treatment of women with PCOS was performed through a systematic literature search using the following databases: MEDLINE (1966 to October 2015), EMBASE (1974 to October 2015), SCISEARCH (1974 to October 2015), Cumulative Index to Nursing and Allied Health Literature (1982 to October 2015), the Cochrane Menstrual Disorders and Subfertility Group trials register (October 2015), Allied and Complementary Medicine (AMED) (1985 to October 2015), China National Knowledge Infrastructure (CNKI) (1982 to October 2015), and the Wanfang database (1982 to October 2015). The reference lists of relevant primary and review articles were also checked to identify further published trials not uncovered in the database search. There were no restrictions placed on language or publication type in the searches. Search terms and key words included: “polycystic ovary morphology” or “polycystic ovary syndrome” or “polycystic ovary” or “ovary polycystic disease” or “PCOS” or “oligo-amenorrhea” or “oligoamenorrhea” or “oligoanovulatory” or “oligohypomenorrhea” or “amenorrhea” or “amenorrhoea” or “hirsutism” AND “acupoint” or “acupressure” or “acupressure-acupuncture therapy” or “acupuncture” or “electro-acupuncture” or “electroacupuncture” or “moxibustion” or “Tui Na” or “ traditional medicine” or “traditional Chinese medicine” or “traditional Chinese medicine combined with western medicine.” All search terms were translated into Chinese terms in order to conduct the searches in Chinese databases. PCOS was diagnosed according to the European Society for Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM) (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004 2004 ). “Acupuncture” was defined as traditional needling acupuncture, auricular acupuncture, electro-acupuncture (EA), auricular acupressure, and warm needling acupuncture. RCTs belonging to one of the following categories were included: (1) acupuncture vs. sham/no intervention; (2) acupuncture+conventional therapy vs. conventional therapy; (3) acupuncture vs. conventional therapy; (4) two or more of the above situations. “Conventional therapy” involved pharmacotherapy for ovulation induction, ethinylestradiol and cyproterone acetate tablets (ECAT), metformin, and Chinese medicinal herbs (CMH). Case reports, reviews, animal experiments, self-control clinical studies, and studies with acupuncture in the control group were excluded. Study selection and data extraction were performed by two authors (FQ and YW) independently, and disagreements were resolved by discussion. Data abstracted from the accepted RCTs included: details of the participants, countries, interventions, outcomes, ethical/institutional review board approval, randomization, single/multi-center, concealment of allocation, blinding, comparability at the baseline, sample size calculation, adverse effects, follow-up and background information about the acupuncture practitioner, which are based upon adherence to the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) (MacPherson et al., 2010 2010 ). Results 1 Main study characteristics 2 A total of 31 RCTs that included 2371 women with PCOS met our inclusion criteria (Yang et al., 2005 2005 ; Zhao et al., 2007 2007 ; Shi et al., 2009 2009 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Li and Han, 2010 2010 ; Cui W. et al., 2011 2011 ; 2012 2012 ; 2015 2015 ; Jedel et al., 2011 2011 ; Li and Zhang, 2011 2011 ; Li Y.L. et al., 2011 2011 ; Pastore et al., 2011 2011 ; Cui Y. et al., 2012 2012 ; Franasiak et al., 2012 2012 ; Liu et al., 2012 2012 ; Johansson et al., 2013 2013 ; Li, 2013 2013 ; Liang et al., 2013a 2013a ; 2013b 2013b ; Rashidi et al., 2013 2013 ; Wang and Gu, 2013 2013 ; Wang and Li, 2013 2013 ; Zhang, 2013 2013 ; Zheng et al., 2013 2013 ; He, 2014 2014 ; Jin et al., 2014 2014 ; Leonhardt et al., 2014 2014 ; Li L. et al., 2014 2014 ; Lin, 2014 2014 ; Liang, 2015a 2015a ; 2015b 2015b ; Qiu et al., 2015 2015 ; Sheng, 2015 2015 ; Wang, 2015 2015 ). A short description of the studies included in this review was shown in Table 1 1 . Of the 31 included trials, three were performed in Sweden (Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Jedel et al., 2011 2011 ; Johansson et al., 2013 2013 ; Leonhardt et al., 2014 2014 ), one in the USA (Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ), one in Iran (Rashidi et al., 2013 2013 ), and all other trials were conducted in China. After the studies were divided into four categories according to interventions, five were identified as “acupuncture vs. sham/no intervention,” fifteen as “acupuncture+conventional therapy vs. conventional therapy,” nine as “acupuncture vs. conventional therapy,” and two as “comparison between different groups containing two or more of the above situations.” PCOS: polycystic ovary syndrome; IVF: in vitro fertilization; ICSI: intra-cytoplasmic sperm injection; BMI: body mass index; FINS: fasting insulin; IRI: insulin resistance index; EA: electro-acupuncture; COH: controlled ovarian hyperstimulation; CMH: Chinese medicinal herbs; CC: clomifene citrate; Gn: gonadotropin; ECAT: ethinylestradiol and cyproterone acetate tablets; HMG: human menopausal gonadotropin; LH: luteotropic hormone; FSH: follicle stimulating hormone; OR: ovulation rate; AMH: anti-Müllerian hormone; MF: menstrual frequency; T: testosterone; MADRS-S: Montgomery-Åsberg depression rating scale-self-rated version; BSA-S: self-reported version of the brief scale for anxiety; SF-36: Swedish short form 36; PCOSQ: polycystic ovary syndrome questionnaire; FPG: fasting plasma glucose; HOMA-IR: homeostasis model assessment for insulin resistance; CPR: clinical pregnancy rate; MR: miscarriage rate; FR: fertilization rate; GQER: good-quality embryo rate; WHR: waist-hip ratio; CR: cleavage rate; LBR: live birth rate; E2: estradiol; P: progesterone; PRL: prolactin; BBT: basal body temperature; IGF-1: insulin-like growth factor-1; TGF-β1: transforming growth factor-beta 1; EGFR: epidermal growth factor receptor; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol Study Participant Country Intervention Control Outcome 6 1. Acupuncture vs. sham/no intervention Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 84 PCOS women aged 18‒43 years without hormonal intervention 60 d before enrollment USA EA Sham acupuncture LH, FSH, OR, longitudinal AMH Jedel et al., 2011 2011 ; Stener-Victorin et al., 2012; 2013; Leonhardt et al., 2014 2014 84 PCOS women aged 18‒37 years Sweden EA (1) Physical exercise (2) No intervention MF, anthropometrics, T, circulating coagulation and fibrinolytic markers, insulin sensitivity (euglycemic hyperinsulinemic clamp), hemodynamics, adipose tissue morphology/function, AMH, antral follicle count, ovarian volume, MADRS-S, BSA-S, SF-36, PCOSQ Johansson et al., 2013 2013 32 PCOS women aged 18‒38 years without any intervention 3 months before enrollment Sweden EA Attention control Anthropometrics, LH, FSH, T, FINS, FPG, HOMA-IR, AMH, inhibin B, cortisol Rashidi et al., 2013 2013 62 PCOS women aged 18‒40 years undergoing IVF/ICSI Iran EA No intervention CPR, ongoing pregnancy rate, MR, metaphase II oocytes rate, FR, GQER Stener-Victorin et al., 2009 2009 20 PCOS women without known endocrine or neoplastic causes of hyperandrogenemia Sweden EA (1) Physical exercise (2) No intervention Muscle sympathetic nerve activity, BMI, WHR, FSH, LH, T, FINS, FPG 6 6 2. Acupuncture+conventional therapy vs. conventional therapy Cui et al., 2015 2015 217 PCOS women undergoing IVF China EA+COH COH Number of oocytes, FR, CR, GQER, CPR, MR, spindle and oocytes quality Cui W. et al., 2011 2011 ; 2012 2012 66 PCOS women undergoing IVF China EA+COH COH Number of oocytes, FR, CR, GQER, CPR, MR, LBR, stem cell factor Li et al., 2011 2011 60 infertile PCOS women without hormonal intervention 90 d before enrollment China Acupuncture+CMH+CC CMH+CC OR, E2, LH, P, endometrial thickness Li et al., 2014 2014 60 PCOS women China Acupuncture+CC CC OR, follicles development, LH Liang et al., 2013a 2013a ; 2013b 2013b 60 infertile PCOS women China Acupuncture+Gn Gn Oocyte maturity, FSH, LH, T, PRL, P, E2 Liang, 2015a 2015a 60 PCOS women China Acupuncture+CC CC FPG, FINS, FSH, LH, T, E2, P, MF, BMI, BBT Liang, 2015b 2015b 80 infertile PCOS women (BMI > 25 kg/m 2 ) without hormonal intervention 90 d before enrollment China Acupuncture+CMH+CC CMH+CC FPG, FINS, FSH, LH, T, E2, P, MF, BMI, OR, CPR Lin, 2014 2014 84 PCOS women aged 19‒35 years China Acupuncture+ECAT ECAT MF, ovarian volume, sex hormone levels Liu et al., 2012 2012 80 PCOS women China Acupuncture+ECAT ECAT FSH, LH, T, PRL, E2, BMI, FINS, FPG Qiu et al., 2015 2015 80 PCOS women aged 16‒40 years China Acupuncture+CMH CMH MF, T, BBT, OR, CPR Sheng, 2015 2015 100 infertile PCOS women resistant to CC China Acupuncture+HMG HMG OR, CPR Shi et al., 2009 2009 63 PCOS women China Acupuncture+CMH CMH FSH, LH, T Wang, 2015 2015 80 infertile PCOS women aged 20‒40 years China Acupuncture+CC CC Number of oocytes, OR, T, LH, E2, FSH, CPR Study Participant Country Intervention Control Outcome Zhang, 2013 2013 60 PCOS women China Acupuncture+ECAT+metformin ECAT+metformin OR, FSH, LH, T Zhao et al., 2007 2007 60 obese PCOS women (BMI > 25 kg/m 2 ) without hormonal intervention 90 d before enrollment China Acupuncture+metformin Metformin BMI, WHR, LH/FSH, T, FINS, FPG, HOMA-IR 6 6 3. Acupuncture vs. conventional therapy Cui Y. et al., 2012 2012 60 PCOS women with normal BMI, FINS and IRI China Acupuncture ECAT OR, FSH, LH, T, IGF-1, TGF-β1, EGFR He, 2014 2014 55 PCOS women aged 21–36 years China Acupuncture CC FSH, LH, T Jin et al., 2014 2014 65 PCOS women China EA ECAT MF, BMI, T, LH, FSH Lai et al., 2010 2010 86 obese PCOS women (BMI > 25 kg/m 2 ) China Abdominal acupuncture Metformin BMI, WHR, Ferriman-Gallwey scale, MF, BMI, T, LH, FSH, FINS, FPG, TC, TG, LDL-C, HDL-C, HOMA-IR Li and Zhang, 2011 2011 60 PCOS women aged 16–40 years without any intervention 6 months before enrollment China EA CC OR, FSH, LH, T, MF Li, 2013 2013 100 PCOS women China Acupuncture+auricular acupressure CC OR, CPR Wang and Li, 2013 2013 78 PCOS women aged 19–32 years China Acupuncture ECAT+CC MF, ovulation Yang et al., 2005 2005 126 infertile PCOS women without hormonal intervention 90 d before enrollment China Acupuncture CC OR, CPR Zheng et al., 2013 2013 86 PCOS women with BMI≥25 kg/m 2 China Abdominal acupuncture Metformin BMI, WHR, ovarian volume, MF, HOMA-IR, Ferriman-Gallwey score, LH, T, FSH, FPG, FINS, TC, triglycerides, LDL-C, HDL-C 6 6 4. Comparison between different groups containing two or more of the above situations Li and Han, 2010 2010 83 PCOS women China (1) Acupuncture (2) Acupuncture+CMH (1) CMH (2) CC MF, ovulation, T, FSH, LH Wang and Gu, 2013 2013 80 PCOS women without hormonal intervention 6 months before enrollment China (1) Acupuncture (2) Acupuncture+CMH (1) CMH (2) CC MF, CPR Study quality of the trials 2 All of the included 31 RCTs were single-center trials. The average number of patients with PCOS was 75, with a range of 20 to 217. In this review, menstrual frequency, hormones, anthropometrics, insulin sensitivity, blood lipids, and fertility were used as the main measurements to assess the effects of acupuncture in treating PCOS. Menstrual frequency and hormones (follicle stimulating hormone (FSH), luteotropic hormone (LH), LH/FSH, and testosterone (T)) were the most common measurements used in evaluating the effect of a therapy on PCOS, and they were available in 25 of the 31 included trials (Zhao et al., 2007 2007 ; Shi et al., 2009 2009 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Li and Han, 2010 2010 ; Jedel et al., 2011 2011 ; Li and Zhang, 2011 2011 ; Li Y.L. et al., 2011 2011 ; Pastore et al., 2011 2011 ; Cui Y. et al., 2012 2012 ; Franasiak et al., 2012 2012 ; Liu et al., 2012 2012 ; Johansson et al., 2013 2013 ; Liang et al., 2013a 2013a ; 2013b 2013b ; Wang and Gu, 2013 2013 ; Wang and Li, 2013 2013 ; Zhang, 2013 2013 ; Zheng et al., 2013 2013 ; He, 2014 2014 ; Jin et al., 2014 2014 ; Leonhardt et al., 2014 2014 ; Li L. et al., 2014 2014 ; Lin, 2014 2014 ; Liang, 2015a 2015a ; 2015b 2015b ; Qiu et al., 2015 2015 ; Wang, 2015 2015 ). Anthropometric measurements, such as body weight, body mass index (BMI), waist, waist-hip ratio (WHR), and the Ferriman-Gallwey score were available in 10 of the 31 included trials (Zhao et al., 2007 2007 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Liu et al., 2012 2012 ; Johansson et al., 2013 2013 ; Zheng et al., 2013 2013 ; Jin et al., 2014 2014 ; Leonhardt et al., 2014 2014 ; Liang, 2015a 2015a ; 2015b 2015b ). Measurements about insulin sensitivity including fasting insulin (FINS), fasting plasma glucose (FPG), and homeostasis model assessment for insulin resistance (HOMA-IR) were available in 9 of the 31 trials (Zhao et al., 2007 2007 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Liu et al., 2012 2012 ; Johansson et al., 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ; Liang, 2015a 2015a ; 2015b 2015b ). Measurements about blood lipids including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were available only in four trials (Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Stener-Victorin et al., 2012 2012 ; 2013 2013 ; Johansson et al., 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ). Only nine trials that used acupuncture in treating infertile women with PCOS had measured ovulation rate (OR), clinical pregnancy rate (CPR), and miscarriage rate (MR) (Yang et al., 2005 2005 ; Cui W. et al., 2011 2011 ; 2012 2012 ; 2015 2015 ; Li, 2013 2013 ; Rashidi et al., 2013 2013 ; Wang and Gu, 2013 2013 ; Qiu et al., 2015 2015 ; Sheng, 2015 2015 ; Wang, 2015 2015 ). More outcomes used in the included trials are shown in Table 1 1 . Acupuncture was used alone in 14 trials (Yang et al., 2005 2005 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Li and Zhang, 2011 2011 ; Pastore et al., 2011 2011 ; Cui Y. et al., 2012 2012 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ; Li, 2013 2013 ; Rashidi et al., 2013 2013 ; Wang and Li, 2013 2013 ; Zheng et al., 2013 2013 ; He, 2014 2014 ; Jin et al., 2014 2014 ; Leonhardt et al., 2014 2014 ), and along with pharmacotherapy for ovulation induction, CMH, ECAT or metformin in the other 17 trials. Among the 31 trials reviewed, blinding was only applied in three RCTs (Stener-Victorin et al., 2009 2009 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ). In one trial, researchers failed to find significant differences in the outcomes between true and sham acupuncture (control) (Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ). In the other 30 trials, there was an improvement in at least one of the indicators of PCOS after acupuncture treatment, when compared with the control group. Reporting quality 2 As shown in Table 2 2 , the reporting quality was evaluated for each of the 31 studies included. In the review, 18 trials (Shi et al., 2009 2009 ; Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Li and Han, 2010 2010 ; Cui W. et al., 2011 2011 ; 2012 2012 ; 2015 2015 ; Jedel et al., 2011 2011 ; Li and Zhang, 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ; Li, 2013 2013 ; Rashidi et al., 2013 2013 ; Wang and Gu, 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ; Li et al., 2014 2014 ; Liang, 2015a 2015a ; 2015b 2015b ; Sheng, 2015 2015 ) described the method of randomization; however, 5 of them were not fully randomized as the sequence was generated by registration order (Lai et al., 2010 2010 ; Li and Han, 2010 2010 ; Wang and Gu, 2013 2013 ; Li et al., 2014 2014 ; Liang, 2015a 2015a ). Six trials had adequate concealment of allocation (Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Jedel et al., 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ; Rashidi et al., 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ). In the present review, only eight trials included information regarding ethical/institutional review board approval (Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ; Rashidi et al., 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ; Sheng, 2015 2015 ). Four trials provided a power analysis and presented a sample size calculation (Jedel et al., 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Stener-Victorin et al., 2012 2012 ; 2013 2013 ; Johansson et al., 2013 2013 ; Rashidi et al., 2013 2013 ; Leonhardt et al., 2014 2014 ). In addition, we found only six trails adhered to STRICTA and reported the acupuncture practitioners (Stener-Victorin et al., 2009 2009 ; 2012 2012 ; 2013 2013 ; Jedel et al., 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Johansson et al., 2013 2013 ; Rashidi et al., 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ). Seven trials in the review provided information regarding adverse effects during the research period (Yang et al., 2005 2005 ; Lai et al., 2010 2010 ; Jedel et al., 2011 2011 ; Stener-Victorin et al., 2012 2012 ; 2013 2013 ; Li, 2013 2013 ; Zheng et al., 2013 2013 ; Leonhardt et al., 2014 2014 ; Li et al., 2014 2014 ; Liang, 2015b 2015b ) and four trials described the follow-up information (Jedel et al., 2011 2011 ; Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 ; Stener-Victorin et al., 2012 2012 ; 2013 2013 ; Wang and Li, 2013 2013 ; Zhang, 2013 2013 ; Leonhardt et al., 2014 2014 ). STRICTA: Standards for Reporting Interventions in Clinical Trials of Acupuncture; ND: not described Study Description of information of ethical approval Randomization method Single-/multi-centre Concealment of allocation Placebo intervention Blinding Comparability at baseline Sample size calculation Acupuncture practitioner Description of adverse effects Follow-up Adherence to STRICTA 13 1. Acupuncture vs. sham/no intervention Pastore et al., 2011 2011 ; Franasiak et al., 2012 2012 Yes A random number generator program Single Adequate Yes Yes Yes Yes Acupuncturist No Yes Yes Jedel et al., 2011 2011 ; Stener-Victorin et al ., 2012; 2013; Leonhardt et al., 2014 2014 Yes Computerized randomization Single Adequate No No Yes Yes Physical therapist Yes Yes Yes Johansson et al., 2013 2013 Yes Computerized randomization Single Adequate Yes Yes Yes Yes Therapist No No Yes Rashidi et al., 2013 2013 Yes Computerized randomization Single Adequate No No Yes Yes Acupuncturist No No Yes Stener-Victorin et al., 2009 2009 Yes Computerized randomization Single Adequate No Yes Yes ND Acupuncturist No No Yes 13 13 2. Acupuncture+conventional therapy vs. conventional therapy Cui et al., 2015 2015 No A random number table Single ND No No Yes ND ND No No No Cui W. et al., 2011 2011 ; 2012 2012 No A random number table Single ND No No Yes ND ND No No No Li et al., 2011 2011 No ND Single ND No No Yes ND ND No No No Li et al., 2014 2014 No Sequence of recruitment Single ND No No Yes ND ND Yes No No Liang et al., 2013a 2013a ; 2013b 2013b No ND Single ND No No Yes ND ND No No No Liang, 2015a 2015a No A random number table Single ND No No Yes ND ND Yes No No Liang, 2015b 2015b No Sequence of recruitment Single ND No No Yes ND ND No No No Lin, 2014 2014 No ND Single ND No No Yes ND ND No No No Liu et al., 2012 2012 No ND Single ND No No ND ND ND No No No Qiu et al., 2015 2015 No ND Single ND No No Yes ND ND No No No Sheng, 2015 2015 Yes A random number table Single ND No No Yes ND ND No No No Shi et al., 2009 2009 No A random number table Single ND No No Yes ND ND No No No Wang, 2015 2015 No ND Single ND No No Yes ND ND No No No Zhang, 2013 2013 No ND Single ND No No Yes ND ND No Yes No Zhao et al., 2007 2007 No ND Single ND No No Yes ND ND No No No 13 13 3. Acupuncture vs. conventional therapy Cui Y. et al., 2012 2012 No ND Single ND No No Yes ND ND No No No He, 2014 2014 No ND Single ND No No ND ND ND No No No Jin et al., 2014 2014 No ND Single ND No No Yes ND ND No No No Lai et al., 2010 2010 Yes Sequence of recruitment Single ND No No Yes ND ND Yes No No Li and Zhang, 2011 2011 No A random number table Single ND No No Yes ND ND No No No Li, 2013 2013 No A random number table Single ND No No Yes ND ND Yes No No Wang and Li, 2013 2013 No ND Single ND No No Yes ND ND No Yes No Yang et al., 2005 2005 No ND Single ND No No Yes ND ND Yes No No Zheng et al., 2013 2013 Yes Computerized randomization Single Adequate No No Yes ND Acupuncturist Yes No Yes 13 13 4. Comparison between different groups containing two or more of the above situations Li and Han, 2010 2010 No Sequence of recruitment Single ND No No Yes ND ND No No No Wang and Gu, 2013 2013 No Sequence of recruitment Single ND No No Yes ND ND No No No Discussion 1 About study quality 2 While single-center trials are excellent for investigating research hypotheses, they also have inherent limitations. In contrast, multi-center trials expand the statistical power, increase generalizability, and moderately affect the sizes to maximize overall robustness. It would be advantageous to conduct more multi-center trials in the future to confirm the generalizability of the interventions. For clinical trials, outcome measurements, whether objective, subjective, or patient-centered, should be disease-specific and follow the international classification of diseases. In this review, a range of objective, subjective, and patient-centered outcome measurements was identified in the included RCTs. Menstrual frequency, ovulation, CPR, and hormones were the most common measurements used in the included trials, and no other measurements were used to assess the effects of acupuncture on patients with PCOS in the several trials. Due to the various clinical manifestations of PCOS, measurements of anthropometry, insulin sensitivity, and blood lipids should be more frequently used. Patient-centered outcome measurements, such as questionnaire scores of life quality among patients with PCOS, should be used in conjunction with conventional measurements. According to the interventions and controls, the included studies were divided into four categories as mentioned above. Among these, “acupuncture vs. sham acupuncture” might be the best design to evaluate the effectiveness of acupuncture on PCOS, as it can eliminate the placebo effects of acupuncture. For an acupuncture treatment, it may be difficult to obtain “ideal” blinding, especially for subjects who have received prior acupuncture. In an RCT that investigates the effects of acupuncture in treating PCOS, blinding should be evaluated at the beginning of the trial to minimize placebo and expectancy effects of acupuncture from verbal and non-verbal communications with enrolled subjects. For an RCT of acupuncture, it may be difficult to find an ideal placebo-control method (Vincent and Lewith, 1995 1995 ; Margolin et al., 1998 1998 ; Tang et al., 1999 1999 ; Emanuel and Miller, 2001 2001 ; Sherman et al., 2004 2004 ). For non-drug interventions including acupuncture, it has been difficult to establish a placebo or sham control that is both inert and indistinguishable (Dincer and Linde, 2003 2003 ). A baseline measurement of the effectiveness of acupuncture in treating PCOS is helpful in determining whether the active acupuncture intervention is superior or equivalent to the placebo-controls. The selection of acupoints and the visual impact of needling are all key factors that can affect the “placebo” response. About reporting quality 2 An important factor in any RCT is randomization. This ensures that the baseline factors of each group are equally distributed. Detailed information on randomization should be provided in future RCTs. As delivery, frequency, and intensity of acupuncture treatment may influence outcomes, such details should be recorded, including the number of needle insertions per subject per session (mean and range where relevant), names (or location if no standard name) of acupoints used (uni/bilateral), depth of insertion based on a specified unit of measurement or on a particular tissue level, response sought (e.g. de qi or muscle twitch response), needle stimulation (e.g. manual, electrical), needle retention time, needle type (diameter, length, and manufacturer or material), number of treatment sessions, frequency and duration of treatment sessions, and details of other interventions administered to the acupuncture group (e.g. moxibustion, cupping, herbs, exercises, lifestyle advice) (MacPherson et al., 2010 2010 ). A minimum of four acupuncture treatment sessions is recommended to obtain satisfactory curative effects when treating PCOS women. These details should be described in future RCTs concerning acupuncture for treating PCOS. For all clinical trials, it is important to obtain ethical/institutional review board approval before initiation. The ethical considerations of the acupuncture trials should be described in detail, including the approval of an institutional review board and date of approval. The sample size of RCTs concerning acupuncture should be calculated a priori based upon previous studies. Insufficient sample size will definitely lead to weakening of the statistical characteristics. To effectively calculate the adequate sample size, it is important to perform and describe an appropriate power calculation, an estimate of drop-out rates and to establish a practical recruitment strategy concerning how patients will be approached and recruited into the trial. STRICTA, a series of guidelines to provide authors a way to structure their reports of acupuncture interventions with a minimum set of items using a checklist, not only facilitates transparency in published reports, but also describes all the necessary details to replicate the trials. The revised STRICTA guideline includes 6 items and 17 sub-items, which set the reporting guidelines for the acupuncture rationale, the details of needling, the treatment regimen, other components of treatment, the practitioner background, and the control or comparator intervention (MacPherson et al., 2010 2010 ). It seems that STRICTA had not yet been taken into account in most of the studies on acupuncture for PCOS. We strongly recommend that STRICTA should be used as the gold standard in designing and reporting the protocol for acupuncture in clinical trials. The preferences and expectation of patients may be contributing factors in the effectiveness of acupuncture. Since high expectations for acupuncture may correlate with high response rates and improved outcomes in the placebo control group, it may be difficult to detect a significant difference between the active acupuncture and placebo control interventions. To address this, a run-in phase stratification for randomization and measurements of expectation should be used in RCTs involving acupuncture. A simple and effective tool to evaluate expectations at baseline is to ask questions such as: “How effective do you consider acupuncture to be in general” with responses that include “very effective, effective, slightly effective, not effective, do not know.” As the experience, expectations and knowledge of acupuncture among patients with PCOS in various countries may influence the effectiveness of acupuncture on PCOS, such information should be taken into consideration and described. For an RCT, safety is of utmost importance. The patients should be instructed to record the time of acupuncture treatment and any adverse effects in a diary. More attention should be paid to adverse effects in the future studies concerning acupuncture for treating PCOS. Although traditional Chinese medicine and acupuncture may have a more gradual time course of effectiveness than pharmacotherapy, these may also provide longer-term and sustained health benefits to patients with PCOS. Consequently, it is necessary to include information related to the follow-up periods that are long enough (at least one year after cessation of treatment) to optimally evaluate the effectiveness of acupuncture in treating patients with PCOS. A long period of follow-up should be performed and described in future trials. As the needling stimulation in traditional Chinese acupuncture is invasive and can be painful, it may lead to higher drop-out rates than non-invasive treatments. Transcutaneous acupoint electrical stimulation (TEAS), a non-invasive acupuncture, may be effective (Zhang R. et al., 2011 2011 ; Zhang Q. et al., 2014 2014 ). For patients with PCOS who are not willing to receive invasive treatment, TEAS may be a more suitable intervention, which is a new development for traditional acupuncture under the advancement of modern science (Zhang R. et al., 2011 2011 ; Zhang Q. et al., 2014 2014 ). Based on review of the evidences for acupuncture treatment for PCOS, we highlighted how future trials can be improved and where efforts should now be focused to improve the evidence base. However, some of these may be a little limited, due to the complexity of this disease, PCOS, and the marked differences on the design of the included trials. References W Cui , J Li , W Sun , 等 . Effect of electroacupuncture on oocyte quality and pregnancy for patients with PCOS undergoing in vitro fertilization and embryo transfer . 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Afr J Tradit Complement Altern Med , 2009 . 6 ( 4 ): 494 - 517 . . Treating gynaecological disorders with traditional Chinese medicine: a review Compliance with ethics guidelines Yan WU, Nicola ROBINSON, Paul J. HARDIMAN, Malcolm B. TAW, Jue ZHOU, Fang-fang WANG, and Fan QU declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1500301 Project supported by the China Scholarship Council (No. 2013083 30139), the Zhejiang Traditional Chinese Medicine Foundation (No. 2015ZQ025), and the Ministry of Health Special Fund of China (No. 201302013) 2015-12-03 2016-02-19 2016-02-15 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2016 2016 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 03 17