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    Metformin for the treatment of the polycystic ovary syndrome. Nestler John E The New England journal of medicine 10.1056/NEJMct0707092
    A 27-year-old woman with a diagnosis of polycystic ovary syndrome. Legro Richard S JAMA Ms R, a 27-year-old woman with polycystic ovary syndrome (PCOS) diagnosed after irregular menses, hirsutism, and polycystic ovaries, is concerned about weight gain despite regular exercise and watching her diet. Prescribed oral contraceptives to regulate her menses and help reduce her androgen levels, she wants to know the alternatives for treatment of PCOS. The varying definitions of PCOS and its heterogeneity confound the interpretation of studies on PCOS. Specific diagnostic criteria have been established based on expert opinion but have not been validated. Several commonly performed laboratory tests are generally unhelpful and the pathophysiology is poorly understood. Treatment options for Ms R, including those that may affect her weight gain, are reviewed and implications for future fertility are discussed. 10.1001/jama.297.5.509
    Increased body iron stores of obese women with polycystic ovary syndrome are a consequence of insulin resistance and hyperinsulinism and are not a result of reduced menstrual losses. Luque-Ramírez Manuel,Alvarez-Blasco Francisco,Botella-Carretero José I,Sanchón Raul,San Millán José L,Escobar-Morreale Héctor F Diabetes care OBJECTIVE:Increased serum ferritin levels, indicating increased body iron stores, have been found in overweight and obese women with polycystic ovary syndrome (PCOS). This finding might result from reduced menstrual losses secondary to oligo- or amenorrhea or from hyperinsulinism secondary to insulin resistance, because insulin favors the intestinal absorption and the tissue deposition of iron. To explore which of these mechanisms is responsible for the increase in body iron stores in women with PCOS, we have monitored the changes in serum ferritin levels during treatment with an antiandrogenic oral contraceptive or an insulin sensitizer. RESEARCH DESIGN AND METHODS:Thirty-four consecutive PCOS patients were randomized to an oral contraceptive containing 35 microg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane(35) Diario) or metformin (850 mg twice daily), and their serum ferritin levels were evaluated at baseline and after 12 and 24 weeks of treatment. RESULTS:Despite the fact that treatment with Diane(35) Diario restored regular menstrual cycles in all the patients, whereas metformin only did so in 50% of them, serum ferritin levels decreased at 12 and 24 weeks of treatment only with metformin, in association with a marked increase in insulin sensitivity. On the contrary, no changes in ferritin and insulin sensitivity were observed with Diane(35) Diario. CONCLUSIONS:Our present results suggest that insulin resistance and hyperinsulinism, and not the reduced menstrual losses secondary to from oligo- or amenorrhea, are responsible of the increased ferritin levels and body iron stores found in overweight and obese women with PCOS. 10.2337/dc07-0642
    Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. Legro Richard S,Barnhart Huiman X,Schlaff William D,Carr Bruce R,Diamond Michael P,Carson Sandra A,Steinkampf Michael P,Coutifaris Christos,McGovern Peter G,Cataldo Nicholas A,Gosman Gabriella G,Nestler John E,Giudice Linda C,Leppert Phyllis C,Myers Evan R, The New England journal of medicine BACKGROUND:The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. METHODS:We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. RESULTS:The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. CONCLUSIONS:Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].). 10.1056/NEJMoa063971
    Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Chen Zi-Jiang,Zhao Han,He Lin,Shi Yuhua,Qin Yingying,Shi Yongyong,Li Zhiqiang,You Li,Zhao Junli,Liu Jiayin,Liang Xiaoyan,Zhao Xiaoming,Zhao Junzhao,Sun Yingpu,Zhang Bo,Jiang Hong,Zhao Dongni,Bian Yuehong,Gao Xuan,Geng Ling,Li Yiran,Zhu Dongyi,Sun Xiuqin,Xu Jin-E,Hao Cuifang,Ren Chun-E,Zhang Yajie,Chen Shiling,Zhang Wei,Yang Aijun,Yan Junhao,Li Yuan,Ma Jinlong,Zhao Yueran Nature genetics Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P-value by meta-analysis P(meta) = 7.55 × 10⁻²¹, odds ratio (OR) 0.71); 2p21 (rs13429458, P(meta) = 1.73 × 10⁻²³, OR 0.67); and 9q33.3 (rs2479106, P(meta) = 8.12 × 10⁻¹⁹, OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended. 10.1038/ng.732
    Polycystic ovary syndrome. Nature reviews. Disease primers 10.1038/nrdp.2016.58
    Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Toulis K A,Goulis D G,Farmakiotis D,Georgopoulos N A,Katsikis I,Tarlatzis B C,Papadimas I,Panidis D Human reproduction update BACKGROUND:Conflicting results regarding adiponectin levels in women with polycystic ovary syndrome (PCOS) have been reported. To evaluate adiponectin levels in PCOS, a systematic review of all studies comparing adiponectin levels in women with PCOS with healthy controls and a meta-analysis of those involving women with similar body mass index (BMI) were performed. The influence of possible effect modifiers, such as insulin resistance (IR) and testosterone, was investigated. The influence of obesity was investigated through a 'nested' meta-analysis after within-study BMI stratification and appropriate pooling. METHODS:Literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL (through June 2008), references from relevant studies and personal contact with the authors. Thirty-one studies, reporting data on 3469 subjects, were reviewed and 16 included in the main meta-analysis. RESULTS:Women with PCOS demonstrated significantly lower adiponectin values [weighted mean difference (95% confidence interval) -1.71 (-2.82 to -0.6), P < 10(-4)], yet with significant between-study heterogeneity. Lower adiponectin levels are associated with the IR observed in women with PCOS, compared with controls. IR, but not total testosterone, was found significant among biological parameters explored in the meta-regression model. Hypoadiponectinaemia was present in both lean and obese women with PCOS when compared with non-PCOS counterparts. Data on high molecular weight (HMW) adiponectin are limited (three studies). CONCLUSIONS:After controlling for BMI-related effects, adiponectin levels seem to be lower in women with PCOS compared with non-PCOS controls. Low levels of adiponectin in PCOS are probably related to IR but not to testosterone. Total adiponectin should not be used as a biomarker of PCOS severity. Further investigation is needed for HMW adiponectin levels in PCOS. 10.1093/humupd/dmp006
    Polycystic ovary syndrome. Norman Robert J,Dewailly Didier,Legro Richard S,Hickey Theresa E Lancet (London, England) Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects about one in 15 women worldwide. The major endocrine disruption is excessive androgen secretion or activity, and a large proportion of women also have abnormal insulin activity. Many body systems are affected in polycystic ovary syndrome, resulting in several health complications, including menstrual dysfunction, infertility, hirsutism, acne, obesity, and metabolic syndrome. Women with this disorder have an established increased risk of developing type 2 diabetes and a still debated increased risk of cardiovascular disease. The diagnostic traits of polycystic ovary syndrome are hyperandrogenism, chronic anovulation, and polycystic ovaries, after exclusion of other conditions that cause these same features. A conclusive definition of the disorder and the importance of the three diagnostic criteria relative to each other remain controversial. The cause of polycystic ovary syndrome is unknown, but studies suggest a strong genetic component that is affected by gestational environment, lifestyle factors, or both. 10.1016/S0140-6736(07)61345-2
    Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Lim S S,Davies M J,Norman R J,Moran L J Human reproduction update BACKGROUND Polycystic ovary syndrome (PCOS) is closely associated with obesity but the prevalence of obesity varies between published studies. The objective of this research was to describe the prevalence of overweight, obesity and central obesity in women with and without PCOS and to assess the confounding effect of ethnicity, geographic regions and the diagnostic criteria of PCOS on the prevalence. METHODS MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL) and PSYCINFO were searched for studies reporting the prevalence of overweight, obesity or central obesity in women with and without PCOS. Data were presented as prevalence (%) and risk ratio (RR) [95% confidence interval (CI)]. Random-effect models were used to calculate pooled RR. RESULTS This systematic review included 106 studies while the meta-analysis included 35 studies (15129 women). Women with PCOS had increased prevalence of overweight [RR (95% CI): 1.95 (1.52, 2.50)], obesity [2.77 (1.88, 4.10)] and central obesity [1.73 (1.31, 2.30)] compared with women without PCOS. The Caucasian women with PCOS had a greater increase in obesity prevalence than the Asian women with PCOS compared with women without PCOS [10.79 (5.36, 21.70) versus 2.31 (1.33, 4.00), P < 0.001 between subgroups). CONCLUSIONS Women with PCOS had a greater risk of overweight, obesity and central obesity. Although our findings support a positive association between obesity and PCOS, our conclusions are limited by the significant heterogeneity between studies and further studies are now required to determine the source of this heterogeneity. Clinical management of PCOS should include the prevention and management of overweight and obesity. 10.1093/humupd/dms030
    Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Misso Marie L,Costello Michael F,Garrubba Marie,Wong Jennifer,Hart Roger,Rombauts Luk,Melder Angela M,Norman Robert J,Teede Helena J Human reproduction update UNLABELLED:BACKGROUND Recent studies suggest that metformin may be more effective in women with polycystic ovary syndrome (PCOS) who are non-obese. The objective here is to determine and compare the effectiveness of metformin and clomiphene citrate for improving fertility outcomes in women with PCOS and a BMI < 32 kg/m(2) (BMI 32 kg/m(2) was used to allow for international differences in BMI values which determine access to infertility therapy through the public health system). METHODS Databases were searched for English language articles until July 2011. INCLUSION CRITERIA:women of any age, ethnicity and weight with PCOS diagnosed by all current criteria, who are infertile; at least 1000 mg of any type of metformin at any frequency, including slow release and standard release, compared with any type, dose and frequency of clomiphene citrate. OUTCOMES:rates of ovulation, live birth, pregnancy, multiple pregnancies, miscarriage, adverse events, quality of life and cost effectiveness. Data were extracted and risk of bias assessed. A random effects model was used for meta-analyses of data, using risk ratios (relative risk). RESULTS The search returned 4981 articles, 580 articles addressed metformin or clomiphene citrate and four randomized controlled trials (RCTs) comparing metformin with clomiphene citrate were included. Upon meta-analysis of the four RCTs, we were unable to detect a statistically significant difference between the two interventions for any outcome in women with PCOS and a BMI < 32 kg/m(2), owing to significant heterogeneity across the RCTs. CONCLUSIONS Owing to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m(2). However, a lack of superiority of one treatment is not evidence for equivalence, and further methodologically rigorous trials are required to determine whether there is a difference in effectiveness between metformin and placebo (or no treatment) or between metformin and clomiphene citrate for ovulation induction in women with PCOS who are non-obese. Until then, caution should be exercised when prescribing metformin as first line pharmacological therapy in this group of women. 10.1093/humupd/dms036
    Polycystic Ovary Syndrome. McCartney Christopher R,Marshall John C The New England journal of medicine 10.1056/NEJMc1610000
    Acupuncture for Infertility in Polycystic Ovary Syndrome. Li Yong Ming JAMA 10.1001/jama.2017.13386
    Acupuncture for Infertility in Polycystic Ovary Syndrome-Reply. Wu Xiao-Ke,Stener-Victorin Elisabet,Zhang Heping JAMA 10.1001/jama.2017.13394
    Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Goodarzi Mark O,Dumesic Daniel A,Chazenbalk Gregorio,Azziz Ricardo Nature reviews. Endocrinology Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of up to 10%. Various diagnostic criteria have been proposed, generally centered around the features of hyperandrogenism and/or hyperandrogenemia, oligo-ovulation and polycystic ovarian morphology. Insulin resistance is present in a majority of cases, with compensatory hyperinsulinemia contributing to hyperandrogenism via stimulation of ovarian androgen secretion and inhibition of hepatic sex hormone-binding globulin production. Adipose tissue dysfunction has been implicated as a contributor to the insulin resistance observed in PCOS. Environmental and genetic factors also have a role in the development of PCOS. The syndrome is associated with numerous morbidities, including infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders. Despite these morbidities, PCOS may be common in our society owing to evolutionary advantages of the syndrome in ancient times, including smaller family sizes, reduced exposure to childbirth-related mortality, increased muscle mass and greater capacity to store energy. The diagnosis of PCOS hinges on establishing key features while ruling out other hyperandrogenic or oligo-ovulatory disorders. Treatment is focused on the goals of ameliorating hyperandrogenic symptoms, inducing ovulation and preventing cardiometabolic complications. 10.1038/nrendo.2010.217
    Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. Legro Richard S,Brzyski Robert G,Diamond Michael P,Coutifaris Christos,Schlaff William D,Casson Peter,Christman Gregory M,Huang Hao,Yan Qingshang,Alvero Ruben,Haisenleder Daniel J,Barnhart Kurt T,Bates G Wright,Usadi Rebecca,Lucidi Scott,Baker Valerie,Trussell J C,Krawetz Stephen A,Snyder Peter,Ohl Dana,Santoro Nanette,Eisenberg Esther,Zhang Heping, The New England journal of medicine BACKGROUND:Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS:In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS:Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS:As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.). 10.1056/NEJMoa1313517
    Understanding variation in prevalence estimates of polycystic ovary syndrome: a systematic review and meta-analysis. Skiba Marina A,Islam Rakibul M,Bell Robin J,Davis Susan R Human reproduction update BACKGROUND:Polycystic ovary syndrome (PCOS) prevalence estimates vary when different diagnostic criteria are applied. Lack of standardization of individual elements within these criteria may contribute to prevalence differences. OBJECTIVE AND RATIONALE:A systematic review of studies reporting prevalence of PCOS, using at least one of the National Institutes of Health (NIH), Rotterdam or Androgen Excess Society (AE-PCOS) criteria, was conducted. The aim was to investigate the impact on prevalence reporting of different definitions of the clinical elements for PCOS diagnosis. SEARCH METHODS:A systematic search of Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Emcare and BIOSIS was conducted. The search was limited to English language and studies published between January 1990 and January 2018. Included articles needed to define PCOS by at least one of the NIH, Rotterdam or AE-PCOS criteria, be of an unselected population and be published as a full text article. Risk-of-bias was assessed. OUTCOMES:A total of 21 studies met the inclusion criteria. The random-effects pooled prevalence of PCOS in studies that used the NIH criteria (7% [95% CI: 6-7%]), was significantly different from that identified in studies that used the Rotterdam criteria (12% [95% CI: 10-15%], P < 0.0001) but not studies that used the AE-PCOS criteria (10% [95% CI: 6-13%], P = 0.075). The pooled estimates for Rotterdam and AE-PCOS were not significantly different from each other (P = 0.201). Pooled prevalence estimates were compared between studies separated on the basis of: oligo-amenorrhoea vs oligo-amenorrhoea plus short cycles, clinical androgen excess requiring hirsutism vs any clinical androgen excess, use of different versions and cut-offs for the Ferriman-Gallwey (F-G) score, and inclusion vs non-inclusion of oral contraceptive users. There were no statistically significant differences for any of these comparisons. There was insufficient information to allow subgroup analyses of definitions of polycystic ovaries. WIDER IMPLICATIONS:Inclusion of ovarian morphology results in statistically significantly higher pooled prevalence estimates for PCOS. Heterogeneity in prevalence estimates for PCOS reflect the broad clinical spectrum of the condition, lack of standardization of the elements within each set of diagnostic criteria and the use of a range of diagnostic cut-offs, as well as potential differences between study populations. The use of different definitions for anovulation and clinical androgen excess did not appear to contribute to differences in the estimated prevalence of PCOS in this study. However, as the number of studies in most of the comparison groups was small, real differences may have been missed. Uncertainty surrounding the diagnosis of PCOS urgently needs to be addressed in order to provide clinicians and their patients with greater diagnostic certainty, and hence reduce inappropriate labelling and the potential psychological harm that may accompany misdiagnosis. 10.1093/humupd/dmy022
    Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Dumesic Daniel A,Oberfield Sharon E,Stener-Victorin Elisabet,Marshall John C,Laven Joop S,Legro Richard S Endocrine reviews Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. 10.1210/er.2015-1018
    Polycystic ovary syndrome. Azziz Ricardo,Carmina Enrico,Chen ZiJiang,Dunaif Andrea,Laven Joop S E,Legro Richard S,Lizneva Daria,Natterson-Horowtiz Barbara,Teede Helena J,Yildiz Bulent O Nature reviews. Disease primers Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder. 10.1038/nrdp.2016.57
    First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. Wang Rui,Li Wentao,Bordewijk Esmée M,Legro Richard S,Zhang Heping,Wu Xiaoke,Gao Jingshu,Morin-Papunen Laure,Homburg Roy,König Tamar E,Moll Etelka,Kar Sujata,Huang Wei,Johnson Neil P,Amer Saad A,Vegetti Walter,Palomba Stefano,Falbo Angela,Özmen Ülkü,Nazik Hakan,Williams Christopher D,Federica Grasso,Lord Jonathan,Sahin Yilmaz,Bhattacharya Siladitya,Norman Robert J,van Wely Madelon,Mol Ben Willem, , Human reproduction update BACKGROUND:Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE:We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS:We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES:IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS:In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS. 10.1093/humupd/dmz029
    Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Escobar-Morreale Héctor F Nature reviews. Endocrinology Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in premenopausal women. Heterogeneous by nature, PCOS is defined by a combination of signs and symptoms of androgen excess and ovarian dysfunction in the absence of other specific diagnoses. The aetiology of this syndrome remains largely unknown, but mounting evidence suggests that PCOS might be a complex multigenic disorder with strong epigenetic and environmental influences, including diet and lifestyle factors. PCOS is frequently associated with abdominal adiposity, insulin resistance, obesity, metabolic disorders and cardiovascular risk factors. The diagnosis and treatment of PCOS are not complicated, requiring only the judicious application of a few well-standardized diagnostic methods and appropriate therapeutic approaches addressing hyperandrogenism, the consequences of ovarian dysfunction and the associated metabolic disorders. This article aims to provide a balanced review of the latest advances and current limitations in our knowledge about PCOS while also providing a few clear and simple principles, based on current evidence-based clinical guidelines, for the proper diagnosis and long-term clinical management of women with PCOS. 10.1038/nrendo.2018.24
    The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Balen Adam H,Morley Lara C,Misso Marie,Franks Stephen,Legro Richard S,Wijeyaratne Chandrika N,Stener-Victorin Elisabet,Fauser Bart C J M,Norman Robert J,Teede Helena Human reproduction update BACKGROUND:Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE:The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHODS:The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOMES:Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed. WIDER IMPLICATIONS:This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS. 10.1093/humupd/dmw025
    The efficacy of Tung's acupuncture for sex hormones in polycystic ovary syndrome: A randomized controlled trial. Cao Yu,Chen He,Zhao Danyang,Zhang Li,Yu Xiaogang,Zhou Xinmin,Liu Zhishun Complementary therapies in medicine BACKGROUND:Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder in reproductive-age women. Tung's acupuncture, a Traditional Chinese Medicine (TCM) treatment, is widely used for PCOS in East Asia, but evidence on its efficacy is rare. The aim of this RCT study was to examine whether the Tung's acupuncture could be a complementary treatment method for PCOS. METHODS:A total of 60 PCOS patients were randomly assigned to a Tung's acupuncture group (n = 30) or a cyproterone acetate/ethinylestradiol (CPA/EE) group (n = 30). Each participant received treatments for 12 weeks to assess the short-term treatment efficacy and then followed up for another 12 weeks to assess the long-term treatment efficacy. The primary outcome examined was change in the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH); the secondary outcomes examined were changes in body mass index (BMI), LH, FSH, total testosterone (TT), ovarian volume, polycystic ovary number and menstrual frequency. RESULTS:Both groups showed significant reductions in the LH/FSH ratio, LH and TT after 12-week treatment (p < 0.001) and 12-week follow-up (p < 0.05). No significant differences existed between the two groups (p > 0.05). Both groups showed significant improvement in BMI, menstrual frequency and polycystic ovary number after 12-week treatment (p < 0.05). CONCLUSION:Compared with CPA/EE, Tung's acupuncture showed no better improvement on LH/FSH ratio for PCOS although it could reduce the ratio. Tung's acupuncture might have some effect on long-term weight control and menstruation frequency. Further studies addressing this study's limitations are recommended. 10.1016/j.ctim.2019.04.016
    Progress of integrative Chinese and Western medicine in treating polycystic ovarian syndrome caused infertility. Song Juan-juan,Yan Miao-e,Wu Xiao-ke,Hou Li-hui Chinese journal of integrative medicine Polycystic ovarian syndrome (PCOS) is one of the most popular diseases that cause menstrual dysfunction and infertility in women. The present paper is a brief retrospection on the progress in treatment of PCOS caused infertility with integrative Chinese and Western medicine (ICWM). It can be seen from these materials that using traditional Chinese medicine (TCM) recipes formulated by Shen-replenishing herbs or acupuncture to reinforce Gan-Shen, regulate Chong-Ren Channels in treating PCOS, stable clinical efficacy could be obtained, with less adverse reaction, though the effect initiated somewhat late. Whereas, when Shen-replenishing recipe and acupuncture are combined with hormone or ovulation promoting drugs of Western medicine, the above-mentioned shortcomings would be overcome. So, this combined therapy is frequently used in clinical practice. 10.1007/s11655-001-0312-9
    Effect of acupoint catgut embedding therapy combined with Chinese medicine for nourishing the kidneys and promoting blood circulation and improving blood glucose and lipid levels as well as the pregnancy rate in obese PCOS patients with infertility. Qin Wenmin,Zhao Kai,Yang Haiyan Experimental and therapeutic medicine In this study, we explored the effect of acupoint catgut embedding combined with Chinese medicine for nourishing kidney and promoting blood circulation as well as improving the glucose and lipid levels and pregnancy rate in obese polycystic ovary syndrome (PCOS) patients with infertility. A total of 62 obese patients with PCOS were randomly divided into three groups, 21 of whom were treated with acupoint catgut embedding combined with Chinese medicine, another 21 with catgut embedding therapy, and 20 only with Chinese medicine. We compared the improvement of clinical symptoms and the glucose and lipid levels in the three groups three months after surgery. We found that the effective rate of obesity treatment, body mass index and waist-to-hip ratio of acupuncture-drug group and catgut embedding group were significantly lower than those of the Chinese medicine group (P<0.05). A comparison between the acupuncture-drug group and catgut embedding group was not statistically significant (P>0.05). The triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels of the three groups were significantly decreased and increased, respectively, following treatment, with the total cholesterol (TC) level being decreased significantly only in the acupuncture-drug group (P<0.05), and the LDL level showing no significant difference (P>0.05). The fast insulins, HOMA-IR, TG, TC levels and periodic cancellation rate of the acupuncture-drug group was significantly reduced compared to those of the catgut embedding group and Chinese medicine group after treatment, whereas the HDL levels, periodic ovulation rate and clinical pregnancy rate were higher (P<0.05). However, a comparison between Chinese medicine group and catgut embedding group was not statistically significant (P>0.05). The incidence rate of luteinized unruptured follicle and ovarian hyper-stimulation syndrome of the three groups showed no statistical difference (P>0.05). In conclusion, the study has shown that acupoint catgut embedding therapy combined with Chinese medicine for nourishing the kidneys and promoting blood circulation and improving blood glucose and lipid levels as well as the pregnancy rate in obese PCOS patients with infertility is useful. 10.3892/etm.2016.3715
    Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway. Qiu Zhixia,Dong Jingjing,Xue Chu,Li Xiaonan,Liu Kang,Liu Baolin,Cheng Jun,Huang Fang Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Polycystic ovary syndrome (PCOS) is a complex gynecological endocrine disease commonly occurred in women of childbearing age. The main hallmark of PCOS includes elevated androgen production and insulin resistance (IR). Liuwei Dihuang Pills (LWDH Pills), a commonly prescribed traditional Chinese medicine (TCM) is widely used as a tonic prescription to treat diabetes, female menopause syndrome and other symptoms with'Kidney-Yin' deficiency. It has been reported the effects LWDH pills on PI3K/Akt signaling pathway in T2DM treatment. Recent studies have also indicated that the treatment of menopausal syndrome may be associated with the ovarian sexual hormone levels regulated by LWDH pills to alleviate female infertility. However, its potential benefits on PCOS have not been fully elucidated. AIM OF THE STUDY:The primary aim of this study was to investigate the alterations of PI3K/Akt pathway in polycystic ovary syndrome-insulin resistance (PCOS-IR) progression induced by letrozole combined with high fat diet (HFD) and then to explore the detailed mechanism of LWDH Pills to alleviate PCOS. MATERIALS AND METHODS:The female Sprague-Dawley rats were continuously treated with letrozole (p.o administration at 1 mg kg·day) and HFD for 21 days to establish the PCOS-IR model. Concurrently, metformin (200 mg kg·day) or LWDH Pills was orally administrated (1.2 or 3.6 g kg·day) to intervene disease progression. The ovarian pathology was evaluated by HE (hematoxylin-eosin) staining. The serum sexual hormones, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, progesterone and fasting insulin (FINS) were determined by radioimmunoassay. The protein expressions of IRS-1, PI3Kp85α, Akt and FoxO1a were analyzed by western blotting, while the mRNA levels of follicle-stimulating hormone receptor (FSHR) and Cyp19a1 in ovarian tissue were measured by qPCR. RESULTS:The upregulated phosphorylation of IRS-1 (S307), down-regulated phosphorylation of PI3Kp85α, Akt, and FoxO1a were significantly reversed by LWDH Pills (3.6 g kg·day) in PCOS-IR rats with up-regulated mRNA levels of FSHR and Cyp19a1 in ovary. Also, the index of insulin resistance was gradually adjusted to normal by LWDH Pills. The serum levels of FSH, estradiol, progesterone levels were significantly raised while LH, testosterone were reduced. The ovarian polycystic changes were alleviated while the atresia follicles were reduced. CONCLUSION:LWDH Pills therapy obviously improved the ovarian polycystic pathogenesis and regained the development of follicles via upregulating Cyp19a1, alleviated insulin resistance through acting on PI3K/Akt signaling pathway. These findings have provided scientific evidence for LWDH Pills to treat PCOS. 10.1016/j.jep.2019.111965
    Clinical effects of Shou-Wu Jiang-Qi Decoction combined acupuncture on the treatment of Polycystic Ovarian Syndrome with kidney deficiency, phlegm and blood stasisness: Study protocol clinical trial (SPIRIT Compliant). Xu Wenting,Tang Mengyu,Wang Jiahui,Wang Lihong Medicine BACKGROUND:Polycystic ovary syndrome (PCOS) is a female endocrine disease with a high incidence. At present, drug treatment is still the main therapeutic strategy for PCOS. Traditional Chinese medicine has a long history in the treatment of menstrual disorders. Shouwu Jiangqi Decoction (SWJQD) is a traditional herbal medicine prescribed in a clinical setting as a remedy for PCOS. Acupuncture also plays an important role in regulating the menstrual cycle and treating PCOS. This study aims to examine the efficacy and safety of the combination of SWJQD and acupuncture in the treatment of PCOS. METHODS:This randomized controlled trial will be conducted with a total of 81 participants diagnosed with PCOS. The participants will be randomly divided into 3 treatment groups: group A will receive SWJQD combined with acupuncture; group B, SWJQD combined with sham acupuncture; and group C, metformin. Each treatment will last 3 months. The primary outcomes include the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and the Oral Glucose Tolerance Test. The secondary outcome measures include sex hormone levels, body mass index, ovulation rate, clinical pregnancy rate, and complete genome sequencing data. Adverse events will be recorded during the intervention and follow-up. RESULTS:This study will investigate whether the combination of SWJQD and acupuncture can alleviate the clinical symptoms and improve insulin resistance in patients with PCOS. The results of this study are expected to provide clinical evidence for the application of the combination of SWJQD and acupuncture in patients with PCOS. TRIAL REGISTRATION:Chinese Clinical Trial Registry: ChiCTR1900028106, ChiMCT1900002826 (registered on December 12, 2019). 10.1097/MD.0000000000019045
    Comparative pharmacokinetics and metabolites study of seven major bioactive components of Shaoyao-Gancao decoction in normal and polycystic ovary syndrome rats by ultra high pressure liquid chromatography with tandem mass spectrometry. Liu Jun-Jin,Cheng Yao,Shao Yun-Yun,Chang Zhuang-Peng,Guo Yi-Ting,Feng Xiao-Juan,Xu Ding,Zhang Jing-Ping,Song Yan,Hou Rui-Gang Journal of separation science A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome. 10.1002/jssc.201900002
    Efficacy of different forms of Guizhi Fuling Wan on reproduction and metabolism in women with polycystic ovary syndrome: A protocol for a meta-analysis of randomized controlled trials. Liu Min,Zhu Hongqiu,Hu Xiaodan,Zhu Ying,Chen Haiyan Medicine BACKGROUND:Polycystic ovary syndrome (PCOS), is a common endocrine disorder in women characterized by increased androgen levels, ovulatory dysfunction, and polycystic ovaries. Western medicine is widely used for the treatment of PCOS, but patient satisfaction is low, largely due to its associated gastrointestinal symptoms of nausea and diarrhea. Guizhi Fuling Wan (GFW) is a traditional Chinese medicine used to remove blood stasis and dissipate phlegm for treating gynecological diseases that was invented by Zhang Zhongjing in the Eastern Han dynasty. In recent years, GFW has been widely used to treat patients with PCOS. This study aims to assess the efficacy and safety of GFW in the treatment of PCOS through a systematic review and meta-analysis. METHODS:All randomized controlled trials connected with GFW targeting PCOS will be searched in the following electronic bibliographic databases from their earliest recorded publications to December 2020 without any language restrictions: MEDLINE, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, Chinese Biological Medicine Database, Wan-fang data, Chinese Technical Periodicals, and other databases. The primary outcomes include Sex hormone levels, ovulation rate, pregnancy rate, and total effective rate. The secondary outcomes were Total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, fasting glucose, fasting insulin, insulin sensitivity index, body mass index, hypertrichosis score, acne score, adverse reactions, etc. Two reviewers will independently conduct cations retrieval, de-duplication, filtering, quality assessment, and data analysis by Endnote X9.1 and Review Manager software (RevMan V.5.3). Meta-analysis and/or subgroup analysis will be performed on the included data. DISCUSSION:This study will investigate the application of GFW in the treatment or prevention of PCOS, and provide a high-quality synthesis to judge whether GFW is an effective and safe intervention for PCOS. PROSPERO REGISTRATION NUMBER:CRD42020192405. 10.1097/MD.0000000000022954
    Developing clinical practice guidelines for Chinese herbal treatment of polycystic ovary syndrome: A mixed-methods modified Delphi study. Lai Lily,Flower Andrew,Moore Michael,Lewith George Complementary therapies in medicine OBJECTIVES:Preliminary evidence suggests Chinese herbal medicine (CHM) could be a viable treatment option for polycystic ovary syndrome (PCOS). Prior to conducting a clinical trial it is important to consider the characteristics of good clinical practice. This study aims to use professional consensus to establish good clinical practice guidelines for the CHM treatment of PCOS. DESIGN AND SETTING:CHM practitioners participated in a mixed-methods modified Delphi study involving three rounds of structured group communication. Round 1 involved qualitative interviews with practitioners to generate statements regarding good clinical practice. In round 2, these statements were distributed online to the same practitioners to rate their agreement using a 7-point Likert scale, where group consensus was defined as a median rating of ≥5. Statements reaching consensus were accepted for consideration onto the guideline whilst those not reaching consensus were re-distributed for consideration in round 3. Statements presented in the guidelines were graded from A (strong consensus) to D (no consensus) determined by median score and interquartile range. RESULTS:11 CHM practitioners in the UK were recruited. After three Delphi rounds, 91 statement items in total had been considered, of which 89 (97.8%) reached consensus and 2 (2.2%) did not. The concluding set of guidelines consists of 85 items representing key features of CHM prescribing for PCOS. CONCLUSIONS:These guidelines can be viewed as an initial framework that captures fundamental principles of good clinical practice for CHM. 10.1016/j.ctim.2015.03.003
    Xiao-Yao-San, a Chinese Medicine Formula, Ameliorates Chronic Unpredictable Mild Stress Induced Polycystic Ovary in Rat. Sun Hao-Yu,Li Quan,Liu Yu-Ying,Wei Xiao-Hong,Pan Chun-Shui,Fan Jing-Yu,Han Jing-Yan Frontiers in physiology Chronic stress induces endocrine disturbance, which contributes to the development of polycystic ovary syndrome (PCOS), a condition that remains a challenge for clinicians to cope with. The present study investigated the effect of Xiao-Yao-San (XYS), a traditional Chinese medicine formula used for treatment of gynecological disease, on the chronic stress-induced polycystic ovary and its underlying mechanism. Female Sprague-Dwaley rats underwent a 3 weeks chronic unpredictable mild stress (CUMS) procedure to establish the PCOS model, followed by 4 weeks treatment with XYS (0.505 g/kg or 1.01 g/kg) by gavage. Granulosa cells were exposed to noradrenaline (1 mM) for 24 h, followed by incubation with or without XYS-treated rat serum for 24 h. Post-treatment with XYS ameliorated CUMS-induced irregular estrous cycles and follicles development abnormalities, decrease of estradiol and progesterone level as well as increase of luteinizing hormone in serum, reduced cystic follicles formation and the apoptosis and autophagy of granulosa cells, attenuated the increase in dopamine beta hydroxylase and c-fos level in locus coeruleus, the noradrenaline level in serum and ovarian tissue, and the expression of beta 2 adrenergic receptor in ovarian tissue. Besides, XYS alleviated the reduction of phosphorylation of ribosomal protein S6 kinase polypeptide I and protein kinase B, as well as the increase of microtubule-associated protein light chain 3-I to microtubule-associated protein light chain 3-II conversion both and . This study demonstrated XYS as a potential strategy for CUMS induced polycystic ovary, and suggested that the beneficial role of XYS was correlated with the regulation of the sympathetic nerve activity. 10.3389/fphys.2017.00729
    Standardised versus individualised multiherb Chinese herbal medicine for oligomenorrhoea and amenorrhoea in polycystic ovary syndrome: a randomised feasibility and pilot study in the UK. Lai Lily,Flower Andrew,Prescott Philip,Wing Trevor,Moore Michael,Lewith George BMJ open OBJECTIVES:To explore feasibility of a randomised study using standardised or individualised multiherb Chinese herbal medicine (CHM) for oligomenorrhoea and amenorrhoea in women with polycystic ovary syndrome (PCOS), to pilot study methods and to obtain clinical data to support sample size calculations. DESIGN:Prospective, pragmatic, randomised feasibility and pilot study with participant and practitioner blinding. SETTING:2 private herbal practices in the UK. PARTICIPANTS:40 women diagnosed with PCOS and oligomenorrhoea or amenorrhoea following Rotterdam criteria. INTERVENTION:6 months of either standardised CHM or individualised CHM, 16 g daily taken orally as a tea. MAIN OUTCOME MEASURES:Our primary objective was to determine whether oligomenorrhoea and amenorrhoea were appropriate as the primary outcome measures for the main study. Estimates of treatment effects were obtained for menstrual rate, body mass index (BMI), weight and hirsutism. Data were collected regarding safety, feasibility and acceptability. RESULTS:Of the 40 participants recruited, 29 (72.5%) completed the study. The most frequently cited symptoms of concern were hirsutism, weight and menstrual irregularity. Statistically significant improvements in menstrual rates were found at 6 months within group for both standardised CHM (mean difference (MD) 0.18±0.06, 95% CI 0.06 to 0.29; p=0.0027) and individualised CHM (MD 0.27±0.06, 95% CI 0.15 to 0.39; p<0.001), though not between group (p=0.26). No improvements were observed for BMI nor for weight in either group. Improvements in hirsutism scores found within group for both groups were not statistically significant between group (p=0.09). Liver and kidney function and adverse events data were largely normal. Participant feedback suggests changing to tablet administration could facilitate adherence. CONCLUSIONS:A CHM randomised controlled trial for PCOS is feasible and preliminary data suggest that both individualised and standardised multiherb CHMs have similar safety profiles and clinical effects on promoting menstrual regularity. These data will inform the design of a study in primary care that will incorporate an appropriate control. TRIAL REGISTRATION NUMBER:ISRCTN 31072075; Results. 10.1136/bmjopen-2016-011709
    Traditional Chinese Medicine formula FTZ protects against polycystic ovary syndrome through modulating adiponectin-mediated fat-ovary crosstalk in mice. Xu Ying,Tang Jialing,Guo Qianyu,Xu Yidan,Yan Kaixuan,Wu Lihong,Xie Kang,Zhu Anming,Rong Xianglu,Ye Dewei,Guo Jiao Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:FuFang ZhenZhu TiaoZhi (FTZ) is a hospitalized traditional Chinese medicine herbal formula with documented metabolic benefits. Polycystic ovary syndrome (PCOS) characterized by ovarian dysfunction and insulin resistance represents one of the most common endocrine disorders in close association with metabolic dysfunction in premenopausal women. AIM OF THE STUDY:The present study aimed to investigate the preventive effect of FTZ on letrozole-induced experimental PCOS and its associated insulin resistance in mice. MATERIALS AND METHODS:Prepubertal female mice in the experimental groups (letrozole and FTZ) received continuous infusion of letrozole (50 μg/day) for 35 days. FTZ was administrated to mice by oral gavage daily at dosage of 2.892 g/kg body weight for 5 weeks. All groups of mice were fed a high-fat diet (HFD). Ovary and adipose tissue were collected from all mice after 5 weeks and adiponectin, testosterone, estradiol, and luteinizing hormone level determined. RESULTS:Letrozole-induced morphological changes in the ovary, including a decreased number of corpora lutea and antral follicles, and increased cystic follicles, were significantly attenuated in FTZ-treated mice. Additionally, FTZ treatment notably reversed PCOS-related disruption of estrous status. PCOS-related insulin resistance was markedly alleviated. Mechanistically, FTZ treatment notably enhanced circulating level and transcriptional abundance of adiponectin in adipose tissue, thereby orchestrating fat-ovary crosstalk. CONCLUSIONS:Our data collectively demonstrate that FTZ exerted preventive benefits in an experimental model of PCOS, at least partially by potentiating the production of adiponectin from adipose tissues. This suggests that FTZ is a promising treatment for PCOS. 10.1016/j.jep.2020.113587
    Effectiveness of co-treatment with traditional Chinese medicine and letrozole for polycystic ovary syndrome: a meta-analysis. Ma Qian-Wen,Tan Yong Journal of integrative medicine BACKGROUND:Polycystic ovary syndrome (PCOS) is an endocrine disease that affects gynecological health. Treatment of PCOS remains a big challenge for clinicians. OBJECTIVE:This meta-analysis was developed to compare the efficacy of co-treatment with traditional Chinese medicine (TCM) and letrozole against letrozole monotherapy in the treatment of PCOS. SEARCH STRATEGY:Randomized controlled trials (RCTs) were electronically retrieved from PubMed, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure and Wanfang Data; related papers that were not available electronically were manually checked. All papers were assessed according to the Cochrane Handbook for Systematic Reviews of Interventions and the valid data were analyzed using Revman software (The Cochrane Collaboration, Copenhagen, Denmark). INCLUSION CRITERIA:We included RCTs that compared co-treatment with TCM and letrozole against letrozole monotherapy in women with PCOS, which was defined by anovulation, biochemical or clinical hyperandrogenemia and polycystic ovaries. We included trials from all sources. DATA EXTRACTION AND ANALYSIS:Two independent reviewers extracted data, and evaluated study quality according to the Cochrane Handbook for Systematic Reviews of Interventions criteria for RCT, including issues of patient randomization, blinding and bias. RESULTS:Eight RCTs, involving a total of 537 patients, were included in the present study. The meta-analysis showed that the cycle ovulation rate, the pregnancy rate and the total effective rate of symptom treatment were higher in treatments combining TCM with letrozole, compared with letrozole monotherapy. Although the rate of luteinizing hormone (LH)/follicle-stimulating hormone (FSH) and the body mass index of the group receiving combined therapy were lower than in letrozole monotherapy, no statistical difference was found in the LH and FSH level between the two groups. CONCLUSION:Available evidence showed that co-treatment with TCM and letrozole was more effective than letrozole monotherapy in the treatment of PCOS. 10.1016/S2095-4964(17)60320-0
    Consensus on the integrated traditional Chinese and Western medicine criteria of diagnostic classification in polycystic ovary syndrome (draft). Yu Jin,Yu Chao-Qin,Cao Qi,Wang Li,Wang Wen-Jun,Zhou Li-Rong,Li Jing,Qian Qiao-Hong Journal of integrative medicine Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder of women, with complex pathogenesis and heterogeneous manifestations. Professor Jin Yu recently wrote an article entitled "Proposal of Diagnosis and Diagnostic Classification of PCOS in Integrated Traditional Chinese and Western Medicine."From this, the Obstetrics and Gynecology branches of the Chinese Association of Integrative Medicine and the China Association of Chinese Medicine collaborated with the Gynecology branch of the Chinese Association for Research and Advancement of Chinese Medicine to draft a report on the consensus of criteria for the diagnosis and classification of PCOS in integrated traditional Chinese and Western medicine. The diagnosis for PCOS includes all three features: (1) oligo-ovulation or anovulation; (2) clinical and/or laboratory evidence of hyperandrogenism;(3) PCOS is classified into four types: types Ia,Ib, IIa, and IIb. Syndrome differentiation types for PCOS in traditional Chinese medicine are as follows: Kidney deficiency with phlegm blockage syndrome, Kidney Yin deficiency with phlegm blockage and blood stasis syndrome, and Kidney deficiency with Liver Qi stagnation syndrome. 10.1016/S2095-4964(17)60331-5
    Serum metabolomics study of Traditional Chinese medicine formula intervention to polycystic ovary syndrome. Lu Caixia,Zhao Xinjie,Li Yan,Li Yanjie,Yuan Chengkun,Xu Fang,Meng Xiaoyu,Hou Lihui,Xu Guowang Journal of pharmaceutical and biomedical analysis Polycystic ovary syndrome (PCOS) is a most common, heterogeneous, complex endocrinopathy disease. Traditional Chinese medicine (TCM) has been used in the treatment of PCOS for many years. However, the mechanism underlying TCM remains obscure and challenging. In this study, 30 PCOS subjects were separated into normoinsulinemic group (NI=13) and hyperinsulinemic group (HI=17), and treated for three menstrual cycles with TCM Formula, Bushen Huatan Formula (BHF). A metabolomics approach based on ultra-high-performance liquid chromatography (UPLC) coupled with linear ion trap Orbi-trap mass spectrometer (LTQ Orbi-trap MS) is used to investigate serum metabolic changes of TCM intervention to PCOS. After BHF intervention for three menstrual cycles, the serum levels of glycerophosphorylethanolamine (GPEA), creatine, creatinine decreased in both NI and HI groups. Furthermore, in NI group, the main manifestation was the changes of phospholipid metabolism. While in HI group, lysine, phenol sulfate, phe-phe etc. decreased, and ornithine, proline, betaine, acetylcholine etc. increased. Combined with clinical biochemical data, BHF was proved effective to PCOS by reducing the inflammatory reaction and oxidative stress. This study also illustrates that the LC-MS based metabolomic approach is a helpful tool to evaluate curative effect and to understand the mechanisms of TCM. 10.1016/j.jpba.2015.12.020
    The prescription patterns of traditional Chinese medicine for women with polycystic ovary syndrome in Taiwan: A nationwide population-based study. Lin Mei-Jiun,Chen Hsiao-Wei,Liu Pi-Hua,Cheng Wei-Jen,Kuo Shun-Li,Kao Ming-Chen Medicine Polycystic ovary syndrome (PCOS) is a common endocrine disease of reproductive-age women, accounting for about 9% to 18% of all women in this age group. Hyperandrogenemia, oligomenorrhea, or amenorrhea or anovulation, and polycystic ovary morphology are the 3 main criteria used to diagnose PCOS currently. Substantial scientific evidence and consensus on treating Taiwanese PCOS was lacking. The aim of this study is to investigate the characteristics and utilization of traditional Chinese medicine (TCM) among Taiwanese women with PCOS.The data used in this study were derived from the Longitudinal Health Insurance Database (LHID 2000 and LHID 2005). Demographic characteristics, TCM usage, the frequency, as well as average daily dose of Chinese herbal formulas and the single herbs prescribed for patients with PCOS, were analyzed. Chinese herbal formulas and the single herbs prescribed for PCOS women during 1999 to 2013 were extracted to build up Chinese Herbal Medicine prescription database.In our study, 66.43% (n = 8205) women sought TCM treatment because of PCOS for infertility or menstrual disorders. The most commonly prescribed Chinese herbal formula was Jia-wei-xiao-yao-san (Supplemented Free Wanderer Powder). The most commonly prescribed single herb was Yi-mu-cao (Leonuri herba). Among top 20 Chinese herbal formulas, Si-wu-tang has the largest average daily dosage (9.60 g).Our study identified the characteristics and prescription patterns of TCM for patients with PCOS in Taiwan. We may need do further longitudinal research for TCM and its long-term response for improvement of pregnancy rate and reduction of metabolic disease rate. 10.1097/MD.0000000000015890
    Acupuncture attenuates hyperglycaemia and improves ovarian function in female rats subjected to continuous light exposure. Kang Xuezhi,Jia Lina,Li Yaming,Zhang Xu Acupuncture in medicine : journal of the British Medical Acupuncture Society OBJECTIVE:Exposure to unnatural light cycles is increasingly associated with obesity and the metabolic syndrome. The purpose of this study was to examine the effects of electroacupuncture (EA) on glucose metabolism and ovarian function in female rats subjected to long-term continuous light exposure. METHODS:Female Sprague-Dawley rats (n=24) were divided into three experimental groups: an LD group that was maintained under a normal light-dark cycle (healthy control); an LL group that was exposed to continuous light for 21 weeks but remained untreated; and an LL+EA group that received EA at ST36 and SP6 during weeks 17 to 21 of continuous light exposure. RESULTS:Oestrous cycles of female rats kept in a continuously lit environment for 21 weeks were disordered and polycystic ovarian syndrome (PCOS)-like changes occurred, accompanied by increased fasting blood glucose (6.23±0.33 vs 5.27±0.40 mmol/L in week 17, p=0.015) and reduced fasting levels of serum testosterone (0.07±0.018 vs 0.12±0.058 ng/L, p=0.043) and insulin (0.89±0.20 vs 1.43±0.46 ng/L, p=0.006). After 5 weeks of EA treatment at ST36 and SP6, ovarian cycle disruption was mitigated and blood glucose levels showed a gradual decline (5.18±0.37 vs 5.80±0.55 mmol/L, p=0.017; and 5.73±0.31 vs 6.62±0.13 mmol/L, p=0.004; in the fourth and fifth weeks of EA treatment, respectively). EA also attenuated the reductions otherwise seen in serum insulin and testosterone levels. CONCLUSION:Prolonged exposure to light can lead to a decline in ovarian and pancreatic function. EA at ST36 and SP6 may reduce abnormally elevated blood glucose levels and improve ovarian and pancreatic hormone levels. 10.1136/acupmed-2016-011137
    Effects of electroacupuncture and Chinese kidney-nourishing medicine on polycystic ovary syndrome in obese patients. Yu Liqing,Liao Yanjun,Wu Huangan,Zhao Jimeng,Wu Luyi,Shi Yin,Fang Jianqiao Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan OBJECTIVE:To explore the effect of electroacupuncture and Chinese kidney-nourishing medicine on insulin (INS), adiponectin (APN), leptin (LEP), and glucolipid metabolism of obese patients with polycystic ovary syndrome (PCOS). METHODS:Sixty-seven obese PCOS patients were randomly divided into two groups. Thirty-three patients in the acupuncture-medicine group were treated three times a week with electroacupuncture at the Tianshu (ST 25), Zhongwan (CV 12), Qi-hai (CV 6), Sanyinjiao (SP 6), Geshu (BL 17), and Ciliao (BL 32) acupoints. They also took the Chinese drug, Tiankui capsule, for 3 months as a course of treatment. Point-taking and treatment in the electroacupuncture group of 34 patients was the same as those in the acupuncture-medicine group. We observed and compared the changes in the obesity-related indexes of body weight (BW), body mass index (BMI), and waist-hip ratio (WHR), as well as fasting plasma glucose (FPG), fasting insulin (FINS), APN, and LEP. RESULTS:BW, BMI, WHR, and FINS decreased and insulin sensitivity index (ISI) and APN were higher in the acupuncture-medicine group than in the electroacupuncture group (P < 0.01). There was no obvious difference in LEP between the two groups (P > 0.05). CONCLUSION:Acupuncture combined with medicine is better than just electroacupuncture for obese PCOS patients by improving obesity-related indexes, insulin sensitivity, and APN level. This indicates that acupuncture-medicine therapy is worth clinical popularization. 10.1016/s0254-6272(13)60166-1
    Acupuncture to improve fertility in Chinese patients with polycystic ovarian syndrome: what was lost? Lee Seung Min Kathy,Jo Junyoung Acupuncture in medicine : journal of the British Medical Acupuncture Society 10.1136/acupmed-2017-011580
    Oriental herbal medicine and moxibustion for polycystic ovary syndrome: A meta-analysis. Kwon Chan-Young,Lee Boram,Park Kyoung Sun Medicine BACKGROUND:Polycystic ovary syndrome (PCOS) is one of the most common disorders of reproductive endocrinology in women of reproductive age. Lifestyle intervention and oral contraceptives are the first-line treatments for PCOS. Recent studies have suggested that complementary and alternative medicine (CAM) therapies including acupuncture, herbal medicine, and mind-body therapy have the potential to alleviate the symptoms and/or pathology of PCOS and to improve the quality of life of women with PCOS. This meta-analysis aimed to quantitatively summarize the efficacy and safety of moxibustion combined with oriental herbal medicine (OHM), common CAM therapies, for treating PCOS. METHODS:Four databases were searched from their inception to June 22, 2018. Randomized controlled trials (RCTs) and quasi-RCTs using both OHM and moxibustion as experimental intervention, and western medication (WM) as control intervention were included. Studies involving OHM plus moxibustion combined with WM as the experimental intervention were also included. The quality of included studies was assessed using risk of bias tool. RESULTS:Owing to the heterogeneity of reporting, meta-analysis was only performed for pregnancy rate, rate of normal biphasic basal body temperature (BBT), and total effective rate (TER). The results showed that compared to the WM group, the OHM combined with moxibustion group was associated with significantly higher pregnancy rate (risk ratio [RR] 1.95, 95% confidence interval [CI] 1.55-2.47; I = 0%), normal biphasic BBT rate (RR 1.66, 95% CI 1.34-2.05; I = 0%), and TER (RR 1.19, 95% CI 1.08-1.31; I = 0%). When OHM combined with moxibustion was used as an adjunctive therapy to WM, pregnancy rate (RR 1.65, 95% CI 1.29-2.11; I = 0%), and TER (RR 1.35, 95% CI 1.13-1.61; I = 43%) were significantly higher than those of the WM group. CONCLUSION:According to current evidence, OHM combined with moxibustion might be beneficial for treating PCOS. Moreover, the treatment might improve the therapeutic effects of conventional WMs including clomiphene citrate, oral contraceptives, and/or metformin. However, the findings should be interpreted with caution, owing to poor methodological quality of the included studies. Further larger, high-quality, rigorous RCTs should be conducted in this regard. 10.1097/MD.0000000000012942
    Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial. Wu Xiao-Ke,Stener-Victorin Elisabet,Kuang Hong-Ying,Ma Hong-Li,Gao Jing-Shu,Xie Liang-Zhen,Hou Li-Hui,Hu Zhen-Xing,Shao Xiao-Guang,Ge Jun,Zhang Jin-Feng,Xue Hui-Ying,Xu Xiao-Feng,Liang Rui-Ning,Ma Hong-Xia,Yang Hong-Wei,Li Wei-Li,Huang Dong-Mei,Sun Yun,Hao Cui-Fang,Du Shao-Min,Yang Zheng-Wang,Wang Xin,Yan Ying,Chen Xiu-Hua,Fu Ping,Ding Cai-Fei,Gao Ya-Qin,Zhou Zhong-Ming,Wang Chi Chiu,Wu Tai-Xiang,Liu Jian-Ping,Ng Ernest H Y,Legro Richard S,Zhang Heping, JAMA Importance:Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective:To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants:A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions:Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures:The primary outcome was live birth. Secondary outcomes included adverse events. Results:Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance:Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration:clinicaltrials.gov Identifier: NCT01573858. 10.1001/jama.2017.7217
    CLINICAL PRACTICE. Polycystic Ovary Syndrome. McCartney Christopher R,Marshall John C The New England journal of medicine 10.1056/NEJMcp1514916