Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome

Mol B.W., Lai S., Rahim A., Bordewijk E.M., Wang R., van Eekelen R., Gurrin L.C., Thornton J.G., van Wely M., Li W.

Abstract Objectives To propose a checklist that can be used to assess trustworthiness of randomized controlled trials (RCTs). Design A screening tool was developed using the four-stage approach proposed by Moher et al. This included defining the scope, reviewing the evidence base, suggesting a list of items from piloting, and holding a consensus meeting. The initial checklist was set-up by a core group who had been involved in the assessment of problematic RCTs for several years. We piloted this in a consensus panel of several stakeholders, including health professionals, reviewers, journal editors, policymakers, researchers, and evidence-synthesis specialists. Each member was asked to score three articles with the checklist and the results were then discussed in consensus meetings. Outcome The Trustworthiness in RAndomised Clinical Trials (TRACT) checklist includes 19 items organised into seven domains that are applicable to every RCT: 1) Governance, 2) Author Group, 3) Plausibility of Intervention Usage, 4) Timeframe, 5) Drop-out Rates, 6) Baseline Characteristics, and 7) Outcomes. Each item can be answered as either no concerns, some concerns/no information, or major concerns. If a study is assessed and found to have a majority of items rated at a major concern level, then editors, reviewers or evidence synthesizers should consider a more thorough investigation, including assessment of original individual participant data. Conclusions The TRACT checklist is the first checklist developed specifically to detect trustworthiness issues in RCTs. It might help editors, publishers and researchers to screen for such issues in submitted or published RCTs in a transparent and replicable manner.

Weibel S., Popp M., Reis S., Skoetz N., Garner P., Sydenham E.

Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a Research Integrity Assessment (RIA) tool for randomized controlled trials (RCTs) for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing ‘Risk of Bias’ aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies. This article is protected by copyright. All rights reserved.

Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L., Piltonen T., Norman R.J., Andersen M., Azziz R., Balen A., Baye E., Boyle J., Brennan L., Broekmans F., et. al.

What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

Dokras A., Saini S., Gibson-Helm M., Schulkin J., Cooney L., Teede H.

To identify gaps in polycystic ovary syndrome (PCOS) knowledge and practice patterns among physicians in North America in response to significant dissatisfaction identified among women with PCOS regarding their diagnosis and treatment experience.Online survey conducted via American College of Obstetrics and Gynecology of gynecologists (ObGyn) and American Society of Reproductive Medicine of reproductive endocrinologists (REI-ObGyn) in 2015-16.Not applicable.None.None.Diagnostic criteria used, key features of PCOS, management practices.Of the 630 surveys completed, 70.2% were ObGyn and 64.4% were females. Overall 27.7% respondents did not know which PCOS diagnostic criteria they used. In a multivariable analysis including physician type, age, gender, and number of patients with PCOS seen annually, REI-ObGyn were less likely compared with ObGyn to report not knowing which criteria they used (adjusted odds ratio, 0.08; 95% confidence interval, 0.04, 0.16). REI-ObGyn were more likely to use the Rotterdam criteria (odds ratio, 2.26; 95% confidence interval, 1.33, 3.82). The majority of respondents recognized the clinical features associated with PCOS; however, over one-third associated "cysts on ovaries" with PCOS. The majority of responders (>85%) were aware of cardiometabolic comorbidities; however, fewer ObGyn were aware of associated depression, anxiety disorders, and reduced quality of life. More REI-ObGyn recommended lifestyle changes compared with ObGyn (56.4% vs. 41.6%).Our large-scale PCOS survey, conducted in response to patient concerns regarding diagnosis and treatment, highlights opportunities for physician education. Focus areas include targeting knowledge of internationally accepted Rotterdam criteria and ensuring consistent care informed by evidence-based guidelines across the reproductive, metabolic, and psychological features of PCOS.

Azziz R., Carmina E., Chen Z., Dunaif A., Laven J.S., Legro R.S., Lizneva D., Natterson-Horowtiz B., Teede H.J., Yildiz B.O.

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. Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Here, Azziz et al. describe the current state of knowledge regarding the epidemiology, pathophysiology, diagnosis, management and future investigational directions of the disorder.

Teede H., Gibson-Helm M., Norman R.J., Boyle J.

Polycystic ovary syndrome (PCOS) is an under-recognized, common, and complex endocrinopathy. The name PCOS is a misnomer, and there have been calls for a change to reflect the broader clinical syndrome.The aim of the study was to determine perceptions held by women and primary health care physicians around key clinical features of PCOS and attitudes toward current and alternative names for the syndrome.We conducted a cross-sectional study utilizing a devised questionnaire.Participants were recruited throughout Australia via professional associations, women's health organizations, and a PCOS support group.Fifty-seven women with PCOS and 105 primary care physicians participated in the study.Perceptions of key clinical PCOS features and attitudes toward current and alternative syndrome names were investigated.Irregular periods were identified as a key clinical feature of PCOS by 86% of the women with PCOS and 90% of the primary care physicians. In both groups, 60% also identified hormone imbalance as a key feature. Among women with PCOS, 47% incorrectly identified ovarian cysts as key, 48% felt the current name is confusing, and 51% supported a change. Most primary care physicians agreed that the name is confusing (74%) and needs changing (81%); however, opinions on specific alternative names were divided.The name "polycystic ovary syndrome" is perceived as confusing, and there is general support for a change to reflect the broader clinical syndrome. Engagement of primary health care physicians and consumers is strongly recommended to ensure that an alternative name enhances understanding and recognition of the syndrome and its complex features.

Brouwers M.C., Kho M.E., Browman G.P., Burgers J.S., Cluzeau F., Feder G., Fervers B., Graham I.D., Grimshaw J., Hanna S.E., Littlejohns P., Makarski J., Zitzelsberger L.

Clinical practice guidelines, which are systematically developed statements aimed at helping people make clinical, policy-related and system-related decisions,[1][1],[2][2] frequently vary widely in quality.[3][3],[4][4] A strategy was needed to differentiate among guidelines and ensure that those

Teede H., Deeks A., Moran L.

Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS.

Bashir S.M., Ali S.I., Rather M.A., Sheikh W.M., Singh H., Nabi S.U., Ganie M.A., Shafi M., Ul Haq Shah M.Z., Bhat J.I., Wani I.A., Hassan S.

Bernot G., Lallemand L., Le Menager C., Ecochard R.

Sundararajan S., Arunakumari P.S., Skellett A.M., Srinivas V.

Key content Hirsutism is the presence of excess terminal hairs in androgen‐dependent areas in women. The Ferriman–Gallwey score is a pictorial tool used to quantify hirsutism. Polycystic ovary syndrome is the most common cause of hirsutism. In patients with an abnormal Ferriman–Gallwey score or local sexual hair growth, with clinical evidence of a hyperandrogenic endocrine disorder, it is important to measure the total testosterone levels using a reliable specialty assay. Methods of hair reduction and removal remain an important part of management. For most patients who do not seek fertility, combined oral contraceptives are considered as first line pharmacological treatment. Learning objectives To be able to undertake an appropriate evaluation of a patient with hirsutism and understand the rationale behind it. To be able to provide guidance on a structured approach in pharmacological management of hirsutism. To understand how to counsel patients on various management options available for the treatment of hirsutism. Ethical issues Given that hirsutism is only rarely due to a life‐threatening condition, should its treatment be available on the NHS free of cost? Can methods of hair removal and reduction used for the treatment of hirsutism be labelled as cosmetic rather than medical treatment?

Bhatia D., Sharma D., Shah K., Alam P., Dewangan H.K.

Defert C., Cartault A., Haffreingue A., Clermidi P., Lefébure C., Olland A., Glenisson M., Deleforterie T., Bourg A., Vérot P., Haraux E., Bousquet M., Schmitt F., Bonnin Y., Bourezma M., et. al.

Waldrop S.W., Buenaventura M., Campoverde Reyes K.J., Stanford F.C.

Wang Y., Ding J., Min Y., Zhang Y., Ming J., Yin T.

AbstractBackgroundPolycystic ovarian syndrome (PCOS) is the most common endocrine disease in women. Many scholars have explored the basic and clinical research of PCOS. However, there is still a lack of research on knowledge structure, bibliometric analysis, and visualization results in the PCOS field.ObjectiveThe main purpose of our study was to analyze the current research status of PCOS and explore hotspots and weak points through social network analysis (SNA) and visualization study, providing ideas and opinions for follow‐up researchers.MethodsReports on PCOS in the literature published from January 2018 to October 2022 were collected from the Web of Science database. Based on the statistics of keywords, a co‐word network was generated and used to calculate network indicators. The current research hotspots and research trends of PCOS were analyzed with descriptive statistics, co‐occurrence analysis, and SNA.ResultsA total of 9282 unique keywords (total frequency 29 847) were obtained from 5828 papers, and 121 high‐frequency keywords were selected with frequencies greater than or equal to 20. Keywords including insulin resistance, hyperandrogenemia, metabolic syndrome, and overweight rank within the top five in the centrality of these keywords. By network calculation, the PCOS SNA network was divided into eight clusters (C1–C8): C1, reproduction; C2, pathogenesis; C3, related diseases; C4, clinical manifestation; C5, hormone regulation; C6, clinical management; C7, new regulatory factors; and C8, gene polymorphism. Clusters 3, 4, and 6 have higher density, and clusters 1, 3, and 4 have higher degree.ConclusionsThis study reveals the research hotspots and structure of PCOS in recent years through SNA and visualization techniques. We conclude that PCOS is closely related to female reproduction. Although the pathogenesis of PCOS is still unclear, insulin resistance may be the key research topic. Hormone regulation is critical for PCOS, and PCOS patients require careful clinical management. We need more research on the genetics of the disease and new regulatory mechanisms. Our findings will provide reliable and valid support to researchers, funders, policymakers, and clinicians.

Zhu S., Huang Z., Chen X., Jiang W., Zhou Y., Zheng B., Sun Y.

Lin L., Shen H., Wang Y.

Background Despite previous clinical studies providing some evidence of an association between metformin treatment and polycystic ovary syndrome(PCOS), these findings remain controversial. To investigate whether the association reflect causality, a two-sample Mendelian randomization (MR) method was conducted. Methods Data from genome-wide association studies were analyzed, with the exposure factor being metformin and the outcome variable being PCOS. The inverse variance weighted(IVW) was used as the primary method for MR analysis. In addition, MR–Egger, weighted median, heterogeneity tests, and sensitivity analyses were performed. Results The initial and validation MR analyses indicated that genetically predicted metformin treatment had no effects on PCOS. Sensitivity analyses provided additional confirmation of the reliability of the MR results. Conclusions Our two-sample MR analysis did not find genetic evidence supporting a significant association between metformin treatment and PCOS.

Escobar-Morreale H.F., Catteau-Jonard S.

Freitas de Medeiros S., Ferreira de Magalhães L., Yamamoto A.K., Souto de Medeiros M.A., Winck de Medeiros C.L., Yamamoto M.M.

Li J., Dai T., Liu Y., Li Y., Chen T., Chen X., Jin L.

Huang S., Wang Z., Yang R., Li R., Qiao J.

IntroductionFemale obesity has been conclusively associated with compromised fertility, adverse pregnancy outcomes and higher risks of obstetric and neonatal complications. However, it remains unclear whether the adverse outcomes observed in IVF treatments among women with obesity are primarily due to obesity itself or to underlying pathologies such as PCOS. Studies investigating the impact of overweight/obesity compared to normal weight in women with PCOS have yielded inconsistent findings.MethodsWe retrospectively analyzed 4083 women with PCOS undergoing the first IVF-ET cycle with antagonist protocol. Among them, 1755 were divided into the normal weight group (18.5 g/m2 ≤ BMI < 24.0 kg/m2), 1398 into the overweight group (24.0 kg/m2 ≤ BMI < 28.0 kg/m2) and 930 into the obese group (BMI ≥ 28.0 kg/m2). The primary outcome was live birth. Other outcomes were cycle parameters, embryological, pregnancy outcomes and birth weight of newborns. We additionally investigated potential associations of maternal BMI as a continuous variable with outcomes for both linear associations and non-linear associations.ResultWomen with overweight and obese had fewer numbers of oocytes retrieved (adjusted B: -0.82 [-1.17 to -0.47] and adjusted B: -1.86 [-2.26 to -1.46], respectively), numbers of 2PN (adjusted B: -0.52 [-0.78 to -0.26] and adjusted B: -1.86 [-2.26 to -1.46]), and numbers of good-quality embryos (adjusted B: -0.34 [-0.57 to -0.12] and adjusted B: -0.88 [-1.13 to -0.62]), compared to the women with normal weight. The live birth rate was 35.7%, 30.6% and 27.2% in the normal weight group, the overweight group and obese group, respectively (adjusted OR:0.76 [0.65 to 0.89]) for overweight verse normal weight, and adjusted OR:0.64 [0.53 to 0.76)] for obese verse normal weight). There were significant associations between higher BMI and adverse outcomes. We did not observe significant non-linear associations between BMI and these outcomes.DiscussionOverweight or obese women with PCOS undergoing IVF-ET experienced lower numbers of oocytes and good quality embryos, reduced rates of live births, and higher rates of miscarriage compared to normal-weight women with PCOS.

Kolanska K., Zerbib E., Dabi Y., Chabbert-Buffet N., Mathieu-d'Argent E., Favier A., Ferrier C., Touboul C., Hamamah S., Daraï E.

Scannell N., Villani A., Moran L., Mantzioris E., Cowan S.

Background/Objectives: A healthy diet is essential for managing Polycystic Ovary Syndrome (PCOS), yet optimal recommendations remain unclear, highlighting the need to explore alternative lifestyle interventions. The Mediterranean diet (MedDiet) supports cardiometabolic health; however, challenges with adherence within this population are unknown. This study examines the acceptability and experiences of an ad libitum MedDiet in women with PCOS, offering recommendations for implementation. Methods: A 12-week MedDiet intervention was conducted with women aged 18–45 years, diagnosed with PCOS and a BMI ≥ 25 kg/m2 (n = 12). Adherence was assessed using the Mediterranean Diet Adherence Screener. Surveys and semi-structured interviews, guided by the Capability, Opportunity, Motivation–Behaviour (COM-B) model, explored participants’ experiences. Thematic analysis identified barriers and facilitators, which were mapped to the COM-B and Theoretical Domains Framework (TDF), with all findings subsequently aligned with the Behaviour Change Wheel to inform implementation strategies. Results: MedDiet adherence significantly improved from baseline to week 12 (Baseline: 4.1 ± 1.8; week 12: 8.3 ± 2.3; p = 0.001), alongside increases in knowledge (p = 0.004), cooking confidence (p = 0.01), and time management (p = 0.01). Adherence factors were mapped to 12 of the 14 TDF domains. Key facilitators included health benefits, reduced weight pressure, educational resources, and simple guidelines. Barriers involved organisation, food availability, and external influences. Effective implementation should integrate MedDiet education, behaviour change support, practical resources, and professional training for nutrition professionals and healthcare providers to support referrals and weight-neutral dietary management. Conclusions: A short-term ad libitum MedDiet is acceptable for women with PCOS. Strategies for patients and healthcare providers, aligned with the intervention functions of education, training, and enablement, are key to supporting adherence.