Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome†‡

Abstract STUDY QUESTION 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? SUMMARY ANSWER 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. WHAT IS KNOWN ALREADY 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rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated.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. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) 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.

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.

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.

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.

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.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive aged women, with a prevalence of between 8 and 13% depending on the population studied and definitions used ( Teede et al. , 2010 ; Azziz et al. , 2016 ). PCOS is complex with reproductive, metabolic and psychological features ( Teede et al. , 2010 ; Azziz et al. , 2016 ). Clinical practice in the assessment and management of PCOS is inconsistent, with key evidence practice gaps, whilst women internationally have highlighted delayed diagnosis and dissatisfaction with care ( Teede et al. , 2014 ; Dokras et al. , 2017 ; Gibson-Helm, et al. , 2017 ). Current guidelines either are limited in breadth, do not follow rigorous best practice in development, have not involved consumers, or are outdated ( Teede et al. , 2011 ; Legro et al. , 2013 ; Conway et al. , 2014 ; Goodman et al. , 2015 ; Balen et al. , 2016 ), resulting in inconsistent guidance for clinicians and women alike. To address these identified gaps, here we summarize the development process and recommendations from the first international evidence-based guideline for the assessment and management of PCOS, bringing together extensive consumer engagement and international collaboration with leading societies and organizations, multidisciplinary experts, and primary care representatives. In this process, the guideline development groups (GDG) unanimously supported the Rotterdam diagnostic criteria ( Group, 2004 ) for adult women. This comprehensive evidence-based guideline builds on prior high-quality guidelines and culminates from a rigorous, Appraisal of Guidelines for Research and Evaluation-II (AGREE-II)-compliant, evidence-based guideline development process. It provides a single source of international evidence-based recommendations (EBR) to guide clinical practice with the opportunity for adaptation in relevant health systems. Together with an extensive translation program, the aim is to reduce worldwide variation in care and promote high-quality service provision to improve health outcomes and quality of life in women with PCOS. The guidelines are supported by a multifaceted international translation program with co-designed resources to enhance the skills of health professionals and empower women with PCOS, with an integrated comprehensive evaluation program.

Best practice evidence-based guideline development methods were applied and are detailed in the full guideline and the technical reports and outlined in Figure 1 and available at https://www.monash.edu/medicine/sphpm/mchri/pcos ( Misso and Teede, 2012 ). The process aligns with all elements of the AGREE-II tool for quality guideline assessment ( Brouwers et al. , 2010 ). This involved extensive evidence synthesis and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework covering evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength ( GRADE working group ). Evidence synthesis methods are outlined in the full guideline and followed best practice ( NHMRC, 2007 , 2009 ; Brouwers et al. , 2010 ; GRADE working group ). Categories include evidence-based or consensus recommendations with accompanying clinical practice points (Table I ). Figure 1 The steps in developing an evidence-based guideline. GDG = guideline development group; PICO = P: patient, problem or population, I: intervention, C: comparison, control or comparator, O: outcome. Reprinted with permissions from Misso and Teede (2012) . Table I Categories of recommendations in the PCOS guideline. EBR Evidence-based recommendations are made where evidence is sufficient to inform a recommendation made by the guideline development group. CCR Clinical consensus recommendations are made in the absence of adequate evidence on PCOS. These are informed by evidence in other populations and are made by the guideline development group, using rigorous and transparent processes. CPP Clinical practice points are made where evidence was not sought and are made where important clinical issues arose from discussion of evidence-based or clinical consensus recommendations. Terms include ‘should’, ‘could’ and ‘should not’ are informed by the nature of the recommendation (evidence or consensus), the GRADE framework, and quality of the evidence and are independent descriptors reflecting the judgment of the multidisciplinary GDG, including consumers. They refer to overall interpretation and practical application of the recommendation, balancing benefits and harms. ‘Should’ is used where benefits of the recommendation exceed harms, and where the recommendation can be trusted to guide practice. ‘Could’ is used where either the quality of evidence was limited or the available studies demonstrate little clear advantage of one approach over another, or the balance of benefits to harm was unclear. ‘Should not’ is used where there is either a lack of appropriate evidence, or the harms may outweigh the benefits. The GRADE of the recommendation is determined by the GDG based on comprehensive structured consideration of all elements of the GRADE framework ( GRADE working group ), including desirable effects, undesirable effects, balance of effects, resource requirements and cost effectiveness, equity, acceptability and feasibility, and includes: *Conditional recommendation against the option; **conditional recommendation for either the option or the comparison; ***conditional recommendation for the option; and ****strong recommendation for the option. Quality of the evidence is categorized according to the number and design of studies addressing the outcome; judgments about the quality of the studies and/or synthesized evidence, such as risk of bias, inconsistency, indirectness, imprecision and any other considerations that may influence the quality of the evidence; key statistical data; and classification of the importance of the outcomes (Table II ). The quality of evidence reflects the extent of confidence in an estimate of the effect to support a particular recommendation ( GRADE working group ) and was largely determined by the expert evidence synthesis team. Table II Quality (certainty) of evidence categories.* High ⊕⊕⊕⊕ Very confident that the true effect lies close to that of the estimate of the effect. Moderate ⊕⊕⊕○ Moderate confidence in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low ⊕⊕○○ Limited confidence in the effect estimate: the true effect may be substantially different from the estimate of the effect. Very Low ⊕○○○ Very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. *Adapted from the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) (GRADE working group). GRADE acknowledges that evidence quality is a continuum; any discrete categorization involves a degree of arbitrariness. Nevertheless, the advantages of simplicity, transparency and clarity outweigh these limitations ( GRADE working group ).

The International Guideline for the Assessment and Management of PCOS and the related translation program aims to provide clinicians with a quality, reliable source of international EBR to guide consistent clinical practice and to empower women with evidence-based information. All recommendations were formulated after an assessment of the best available evidence, multidisciplinary clinical expertise, consumer preferences and structured review by the five GDGs. Detailed methods for stakeholder engagement and guideline development can be found at https://www.monash.edu/medicine/sphpm/mchri/pcos . The guideline provides 166 recommendations: EBR = 31, clinical consensus recommendations (CCR) = 59, and clinical practice points (CPP) = 76. Overall, evidence is of low to moderate quality, requiring significant research expansion in this neglected, yet common condition. We endorse the Rotterdam PCOS Diagnostic Criteria in adults (two of oligo- or anovulation, clinical and/or biochemical hyperandrogenism, or polycystic ovaries on ultrasound), after exclusion of related disorders. Where both oligo- or anovulation and hyperandrogenism are present, ultrasound is not necessary for diagnosis. In adolescents, both oligo-anovulation and hyperandrogenism are required, with ultrasound not recommended for diagnosis. Ultrasound criteria are refined with advancing technology. Anti-Müllerian hormone levels are not yet adequate for diagnosis of PCOS. Insulin resistance is recognized as a key feature of PCOS, yet clinical measurement is not recommended at the current time. Once diagnosed, assessment and management includes reproductive, metabolic, and psychological features. Education, self-empowerment, multidisciplinary care and lifestyle intervention for prevention or management of excess weight are prioritized. Depressive and anxiety symptoms should be screened, assessed and managed, and health professionals should be aware of other impacts on emotional wellbeing and quality of life. Combined oral contraceptive pills are first-line pharmacological management for menstrual irregularity and hyperandrogenism, with no specific formulation recommended and with low-dose preparations preferred. Metformin is recommended in addition or alone, primarily for management of metabolic features. Letrozole is first-line pharmacological infertility therapy; with clomiphene and metformin both having a role, alone and in combination. In women with PCOS and anovulatory infertility, gonadotrophins are second line. In the absence of an absolute indication for IVF, women with PCOS and anovulatory infertility could be offered IVF third line where other ovulation induction therapies have failed. The combined effects of the provision of a single source of evidence-based recommendations and a comprehensive international translation and dissemination program will amplify the impact of the guideline and recommendations globally. It will support and build the capability of health professionals to deliver high-quality, evidence-based assessment and management of PCOS and will augment the health literacy and self-management of PCOS health consumers. The guideline recommendations are protected under copyright, however the process for adaption of guideline recommendations to the regional context is available at https://www.monash.edu/medicine/sphpm/mchri/pcos . The guideline and translation program will contribute to early diagnosis and improved health outcomes, and promote best-practice PCOS models of care. The translation program will be inclusive of a range of outputs such as the first evidence-based PCOS APP (AskPCOS), a rigorously developed question prompt list to optimize health professional engagement, health literacy enhancing tools, comprehensive PCOS-related health information; internationally accessible health professional accredited courses, webinars with international expert panels, and e-health information resources available at https://www.monash.edu/medicine/sphpm/mchri/pcos . Most importantly, the guideline and translation of the guideline is expected to improve patient experiences through the provision of timely and accurate diagnosis, accessible evidence-based information and improved multidisciplinary support. Ultimately, this initiative may serve as an exemplar for international collaborative engagement and healthcare impact. Key elements included extensive collaboration, broad stakeholder representation, including consumer partnership, distributive leadership, adequate funding, robust project management and governance, adherence to best practice and integrated comprehensive translation and evaluation.

The Australian National Health and Medical Research Council (NHMRC) (APP1078444) funded this work, supported by European Society of Human Reproduction and Embryology (ESHRE) and American society for Reproductive Medicine (ASRM).