Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of PCOS PDF

Human Reproduction, 2023, 38(9), 1655–1679 https://doi.org/...

Human Reproduction, 2023, 38(9), 1655–1679 https://doi.org/10.1093/humrep/dead156 Advance Access Publication Date: August 14, 2023 ESHRE Pages Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome† Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 1,2, Helena J. Teede *, Chau Thien Tay1,2, Joop Laven2,3, Anuja Dokras4, Lisa J. Moran 1,2 , Terhi T. Piltonen 5 , 2,6 7 8 2,9 2,10 1 Michael F. Costello , Jacky Boivin , Leanne M. Redman , Jacqueline A. Boyle , Robert J. Norman , Aya Mousa , Anju E. Joham1,2, on behalf of the International PCOS Network# 1 Monash Centre for Health Research and Implementation, Monash University and Monash Health, Melbourne, Victoria, Australia 2 National Health and Medical Research Council Centre for Research Excellence in Women’s Health in Reproductive Life, Australia 3 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, The Netherlands 4 Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 5 Department of Obstetrics and Gynaecology, Medical Research Center Oulu, Research Unit of Clinical Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland 6 University of New South Wales, New South Wales, Australia 7 Cymru Fertility and Reproductive Research, School of Psychology, Cardiff University, Cardiff, Wales, United Kingdom 8 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A. 9 Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia 10 Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia *Correspondence: Helena J. Teede, Locked Bag 29, Clayton, Australia, 3168, VIC, Australia. E-mail: [email protected]. https://orcid.org/0000-0001- 7609-577X † This article is simultaneously published in Fertility and Sterility, Journal of Clinical Endocrinology and Metabolism, European Journal of Endocrinology and Human Reproduction. # Participants of the International PCOS Network are listed in the Appendix. ABSTRACT STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recom- mendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared prior- ities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across pro- fessional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclu- sion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gy- naecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on Received: July 26, 2023. Editorial decision: July 26, 2023. V C The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 1656 | Teede et al. international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (
6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Mu € llerian hormone (AMH) levels as an alter- native to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, car- diovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional edu- cation, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertil- ity management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains gener- ally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adapta- Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 tion provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients 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): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fel- lowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker’s fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker’s fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker’s fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker’s fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker’s fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organiza- tions, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC. Keywords: Polycystic ovary syndrome / guideline / evidence-based / assessment / management / GRADE What does this mean for those with PCOS? Building on the 2018 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome (PCOS), this Guideline updates and expands clinical questions, aiming to ensure that women with PCOS receive opti- mal, evidence-based care that meets their needs and improves health outcomes. The guideline and translation program were developed with full consumer participation at all stages including priority topics and outcomes for those with PCOS. The aim is to support women and their healthcare providers to optimize diagnosis, assessment and management of PCOS. There is an em- phasis on improved education and awareness of healthcare professionals, partnership in care, and empowerment of women with PCOS. Personal characteristics, preferences, culture and values are considered, in addition to resource availability across different settings. With effective translation, the Guideline will address priorities identified by women with PCOS, upskill health- care professionals, empower consumers, improve care and outcomes, identify key research gaps, and promote vital fu- ture research. Introduction metabolic, and psychological features (Teede et al., 2010; Polycystic ovary syndrome (PCOS) is the most common endocrin- Azziz et al., 2016). Women internationally experience delayed opathy affecting reproductive-aged women, with impacts across diagnosis and dissatisfaction with care (Gibson-Helm er al., 2017; the lifespan from adolescence to post menopause. PCOS preva- Dokras et al., 2017; Teede et al., 2014). Clinical practice in the lence is between 10 to 13%, as confirmed in the guideline process assessment and management of PCOS remains inconsistent, with (Teede et al., 2010; Azziz et al., 2016). PCOS aetiology is complex; ongoing key evidence-practice gaps. Following on from the 2018 and clinical presentation is heterogeneous with reproductive, International Evidence-based Guideline for the Assessment and  International PCOS Guideline 2023 | 1657 Management of Polycystic Ovary Syndrome (Teede et al., 2018a; review, and independent experts reviewed methods, which were Teede et al., 2018b), independently evaluated as high quality, this then submitted to NHMRC for independent review. The target au- extensive update integrates current literature with previous sys- dience includes multidisciplinary healthcare professionals, con- tematic reviews and extends to new clinical questions prioritized sumers or patients, policy makers, and educators. The Guideline by consumers. Ultimately, we aim to update, extend and trans- includes a focus on equity, cultural and ethnic diversity, avoid- late rigorous, comprehensive evidence-based guidelines for diag- ance of stigma and inclusivity (see full guideline for details). nosis, assessment and treatment, to improve the lives of those Processes aligned with all elements of the AGREE-II tool for with PCOS worldwide. quality guideline assessment (Brouwers er al., 2010), with exten- To do so, the Guideline leverages substantive government and sive evidence synthesis and meta-analysis. Integrity assessment society investment and brings together extensive consumer en- was integrated into guideline evidence synthesis processes gagement and international collaboration with leading societies and followed the Research Integrity in Guideline Development and organizations, multidisciplinary experts, and primary care (RIGID) framework, with studies assessed against criteria representatives. This comprehensive evidence-based Guideline is from the Research Integrity Assessment (RIA) tool and the constructed from a rigorous, Appraisal of Guidelines for Research Trustworthiness in RAndomised Controlled Trials (TRACT) check- list (Mousa et al., 2023; Weibel at al., 2023; Mol et al., 2023). Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 and Evaluation-II (AGREEII)-compliant, evidence-based guideline development process. It provides a single source of international Evidence synthesis methods are outlined in the full guideline and evidence-based recommendations to guide clinical practice, with followed best practice (Brouwers et al., 2010; National Health and the opportunity for adaptation in relevant health systems. Medical Research Council, 2009; National Health and Medical Together with an extensive translation program, the aim is to re- Research Council, 2007). Guideline recommendations are pre- duce worldwide variation in care and promote high quality clini- sented by category, terms used, evidence quality and Grading of cal service provision to improve health outcomes and quality of Recommendations, Assessment, Development and Evaluation life in women with PCOS. The Guideline is supported by a multi- (GRADE) framework considerations. Category includes evidence- faceted international translation program with co-designed based (sufficient evidence in PCOS) or consensus (insufficient evi- resources to enhance the skills of healthcare professionals and to dence in PCOS, also evidence in general or relevant populations empower women with PCOS, with an integrated comprehensive was considered) recommendations and accompanying practice evaluation program. Here, we summarize recommendations points (implementation considerations) (Table 1). from the 2023 International Evidence-based Guideline for the The terms include “should”, “could” and “should not”, which Assessment and Management of PCOS. are informed by the nature of the recommendation (evidence or consensus), the GRADE framework and the evidence quality and are independent descriptors reflecting GDG judgement. They Materials and methods refer to overall interpretation and practical application of the Best practice evidence-based guideline development methods recommendation, balancing benefits and harms. “Should” is were applied and are detailed in the full Guideline and the techni- used where benefits of the recommendation exceed harms and cal report, which are available online (www.monash.edu/medi where the recommendation can be trusted to guide practice. cine/mchri/pcos) (Misso and Teede, 2012). In brief, extensive Conditional recommendations are reflected using the terms healthcare professional and consumer or patient engagement in- “could” or “should/could consider” which are used where formed the Guideline priority areas. International society- evidence quality was limited or available studies demonstrate lit- nominated panels from across three leading entities, four partner tle clear advantage of one approach over another, or the balance organizations and thirty-two collaborating entities, included con- of benefits to harms was unclear. “Should not” applies when there sumers and experts in paediatrics, endocrinology, gynaecology, is a lack of appropriate evidence, or harms may out- primary care, reproductive endocrinology, psychology, dietetics, weigh benefits. exercise physiology, sleep, bariatric/metabolic surgery, public Evidence quality was categorized according to the GRADE health, other co-opted experts, project management, evidence framework, with judgments about the quality of the included synthesis and translation. Governance included an international studies and/or synthesized evidence incorporating risk of bias, in- advisory and a management committee, five guideline develop- consistency, indirectness, imprecision and any other considera- ment groups (GDGs) with 56 members, and paediatric, consumer, tions (e.g., publication bias) that may influence evidence quality. and translation committees. The five GDGs covered i) Screening, These judgments considered study number and design, statistical diagnostic and risk assessment and life stage; ii) Psychological data and importance of outcomes (Table 2). The quality of evi- features and models of care; iii) Lifestyle management; iv) dence reflects the confidence that the estimate of the effect is Management of nonfertility features; and v) Assessment and management of infertility. The leading entities; the Australian Table 1. Categories of PCOS guideline recommendations National Health and Medical Research Council (NHMRC) Centres EBR Evidence Based Recommendations: Evidence sufficient to in- for Research Excellence in Women’s Health in Reproductive Life form a recommendation made by the guideline develop- and in Polycystic Ovary Syndrome, led by Monash University, ment group. partnered with the American Society for Reproductive Medicine, CR Consensus Recommendations: In the absence of adequate the Endocrine Society, the European Society of Endocrinology and evidence, a consensus recommendation has been made by the European Society of Human Reproduction and Embryology the guideline development group, also informed by evidence and collaborated with 32 other entities. With international meet- from the general population. ings over 12 months fifty-five prioritized clinical questions in- PP Practice Points: Evidence not sought. A practice point has volved 52 systematic and three narrative reviews, generating been made by the guideline development group where im- evidence-based and consensus recommendations with accompa- portant issues arose from discussion of evidence-based or consensus recommendations. nying practice points. Committee members nominated by partner and collaborator organizations provided international peer PCOS, polycystic ovary syndrome. 1658 | Teede et al. Table 2. Quality (certainty) of evidence categories (adapted Table 3. The Grading of Recommendations, Assessment, from GRADE) Development, and Evaluation (GRADE) framework recommendation strength High 丣丣丣丣 Very confident that the true effect lies close to that of the estimate of the effect. ❖ Conditional recommendation against the option. Moderate 丣丣丣 Moderate confidence in the effect estimate. The true effect is likely to be close to the es- ❖❖ Conditional recommendation for either the op- timate of the effect, but there is a possibil- tion or the comparison. ity that it is different. ❖❖❖ Conditional recommendation for the option. Low 丣丣 Limited confidence in the effect estimate. The true effect may be substantially differ- ❖❖❖❖ Strong recommendation for the option. ent from the estimate of the effect. Very Low 丣 Very little confidence in the effect estimate. Two algorithms are provided to support recommendations on The true effect is likely to be substantially different from the estimate of the effect. diagnosis (Figure 1) and infertility management (Figure 2). Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 GRADE, Grading of Recommendations, Assessment, Development, and Evaluation. Discussion The International Evidence-based Guideline for the Assessment adequate to support each recommendation (National Health and and Management of PCOS and the related translation program Medical Research Council, 2009), largely determined by the expert aims to provide a high quality, reliable source of international evidence synthesis team. GRADE acknowledges that evidence evidence-based recommendations to guide consistent clinical quality is a continuum; any discrete categorization involves some practice and to empower women with evidence-based informa- arbitrary decisions; nevertheless, the advantages of simplicity, tion. All recommendations were formulated after an assessment transparency, and clarity outweigh these limitations (National of the best available evidence, multidisciplinary clinical expertise, Health and Medical Research Council, 2009). consumer preferences and structured review by five GDGs. The The GRADE framework enabled structured and transparent guideline provides 77 evidence-based and 54 consensus recom- consideration across evidence quality, feasibility, acceptability, mendations, with 123 practice points underpinned by a technical cost, implementation, and ultimately recommendation strength report on evidence synthesis and GRADE detailed considerations (National Health and Medical Research Council, 2009) and was (
6000 pages). The evidence has generally improved over the past completed at face to face guideline group meetings for all clinical five years but remains of low to moderate quality, requiring sig- questions (Table 3) (GRADE). nificant research investment into this neglected, yet com- Notably, certainty of evidence varied across outcomes within mon condition. each question. Here evidence certainty reflects the lowest cer- Key recommendations and updates include that PCOS should tainty for the critical outcomes. Evidence was often stronger for be diagnosed using the 2018 International Evidence-based the top ranked outcome, and high quality randomized controlled Guideline criteria, which built on the consensus based 2003 trials (RCTs) were often present, despite overall low quality of evi- Rotterdam criteria. This requires the presence of two of the fol- dence. These nuances were considered by the GDG for all ques- lowing: i) clinical/biochemical hyperandrogenism; ii) ovulatory tion as per the technical report, with any apparent discrepancy dysfunction; and iii) polycystic ovaries on ultrasound; and here in 2023, alternatively anti-Mu € llerian hormone (AMH) can now be between recommendation strength and evidence certainty justi- used instead of ultrasound. Exclusion of other aetiologies is fied in the full Guideline. Finally, we note that this is a living needed. Importantly, where irregular menstrual cycles and Guideline with annual evidence review in rapidly evolving areas. hyperandrogenism are present, diagnosis is simplified and ultra- The recommendations (Table 4) apply the category, descriptive sound or AMH are not required for diagnosis. In adolescents, both terms, GRADE of the recommendations and the quality of the evi- hyperandrogenism and ovulatory dysfunction are required, with dence. The full Guideline, technical evidence and administrative ultrasound and AMH not recommended due to poor specificity. reports are available online (www.monash.edu/medicine/mchri/ AMH was highlighted as a rapidly evolving area in 2018 and evi- pcos). The Guideline outlines the clinical need for the question, dence is now strong enough to make this new recommendation. the clinical question, the evidence summary, the recommenda- This will significantly change practice and offers women a low tions and practice points, and a summary of the justification de- cost, convenient option, without evidence of overdiagnosis. veloped by the GDGs using the GRADE framework. Extensive Insulin resistance is recognized as a key feature of PCOS, yet international peer review from across the 39 organizations was routinely available measures of insulin resistance are inaccurate then considered by each GDG and recommendations were recon- and clinical measurement is not currently recommended. Once sidered applying the GRADE framework if justified. The compre- diagnosed, assessment and management should address repro- hensive evidence reviews, profiles, and GRADE frameworks ductive, metabolic, cardiovascular, dermatologic, sleep, and psy- supporting each recommendation can be found in the Technical chological features. A lifelong health plan is recommended Report. The administrative report on guideline development, dis- including a focus on healthy lifestyle, prevention of excess weight closure of interest process and declarations, peer review feedback gain, optimization of fertility and preconception risk factors, and and responses can also be found online. Here, we present the prevention and treatment of diverse clinical features. These in- evidence-based and consensus recommendations and practice clude metabolic risk factors, diabetes, cardiovascular disease, points (Table 4). This summary, the full Guideline and technical and sleep disorders, which are all increased in PCOS. PCOS should reports are supported by a comprehensive co-designed transla- be considered a high-risk condition in pregnancy with women tion program to optimize dissemination and impact with resour- identified and monitored. An increased premenopausal risk of en- ces freely available online (www.monash.edu/medicine/ dometrial cancer should also be recognized, whilst absolute risks mchri/pcos). remain low.  International PCOS Guideline 2023 | 1659 Table 4. Recommendations for the assessment and management of polycystic ovary syndrome (PCOS). V C Monash University on behalf of the NHMRC Centre for Research Excellence in Women's Health in Reproductive Life 2023. NO. TYPE RECOMMENDATION GRADE/QUAITY 1 Screening, diagnostic and risk assessment and life-stages General principles PP All diagnostic assessments are recommended for use in accordance with the diagnostic algorithm (Algorithm 1). 1.1 Irregular cycles and ovulatory dysfunction 1.1.1 CR Irregular menstrual cycles are defined as: ❖❖❖❖ Normal in the first year post menarche as part of the pubertal transition. 1 to < 3 years post menarche: < 21 or > 45 days. 3 years post menarche to perimenopause: < 21 or > 35 days or < 8 cycles per year. 1 year post menarche > 90 days for any one cycle. Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 Primary amenorrhea by age 15 or > 3 years post thelarche (breast development). When irregular menstrual cycles are present a diagnosis of PCOS should be considered and assessed according to these PCOS Guidelines. 1.1.2 PP The mean age of menarche may differ across populations. 1.1.3 PP In adolescents with irregular menstrual cycles, the value and optimal timing of assess- ment and diagnosis of PCOS should be discussed with the patient and their parent/s or guardian/s, considering diagnostic challenges at this life stage and psychosocial and cul- tural factors. 1.1.4 PP For adolescents who have features of PCOS, but do not meet diagnostic criteria, an “in- creased risk” could be considered and reassessment advised at or before full reproductive maturity, 8 years post menarche. This includes those with PCOS features before combined oral contraceptive pill (COCP) commencement, those with persisting features and those with significant weight gain in adolescence. 1.1.5 PP Ovulatory dysfunction can still occur with regular cycles and if anovulation needs to be confirmed serum progesterone levels can be measured. 1.2 Biochemical hyperandrogenism 1.2.1 EBR Healthcare professionals should use total and free testosterone to assess biochemical ❖❖❖❖ hyperandrogenism in the diagnosis of PCOS; free testosterone can be estimated by the 丣 calculated free androgen index. 1.2.2 EBR If testosterone or free testosterone is not elevated, healthcare professionals could consider ❖❖❖ measuring androstenedione and dehydroepiandrosterone sulfate (DHEAS), noting their 丣 poorer specificity and greater age associated decrease in DHEAS. 1.2.3 EBR Laboratories should use validated, highly accurate tandem mass spectrometry (LC-MS/MS) ❖❖❖❖ assays for measuring total testosterone and if needed, for androstenedione and DHEAS. 丣丣 Free testosterone should be assessed by calculation, equilibrium dialysis or ammonium sulfate precipitation. 1.2.4 EBR Laboratories should use LC-MS/MS assays over direct immunoassays (e.g., radiometric, ❖❖❖❖ enzyme-linked, etc.) for assessing total or free testosterone, which have limited accuracy 丣丣 and demonstrate poor sensitivity and precision for diagnosing hyperandrogenism in PCOS. 1.2.5 PP For the detection of hyperandrogenism in PCOS, the assessment of biochemical hyperan- drogenism is of greatest value in patients with minimal or no clinical signs of hyperandro- genism (i.e., hirsutism). 1.2.6 PP It is very difficult to reliably assess for biochemical hyperandrogenism in women on the com- bined oral contraceptive pill (COCP) as the pill increases sex hormone-binding globulin and reduces gonadotrophin-dependent androgen production. If already on the COCP, and assess- ment of biochemical androgens is imperative, the pill should be withdrawn for a minimum of three months and contraception should be managed otherwise during this time. 1.2.7 PP Repeated androgen measures for the ongoing assessment of PCOS in adults have a lim- ited role. 1.2.8 PP In most adolescents, androgen levels reach adult ranges at 12-15 years of age 1.2.9 PP If androgen levels are markedly above laboratory reference ranges, causes of hyperandro- genaemia other than PCOS, including ovarian and adrenal neoplastic growths, congenital adrenal hyperplasia, Cushing’s syndrome, ovarian hyperthecosis (after menopause), iatro- genic causes, and syndromes of severe insulin resistance, should be considered. However, some androgen-secreting neoplasms are associated with only mild to moderate increases in androgen levels. The clinical history of time of onset and/or rapid progression of symp- toms is critical in assessing for an androgen-secreting tumour. (continued) 1660 | Teede et al. Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 1.2.10 PP Reference ranges for different methods and laboratories vary widely, and are often based on an arbitrary percentile or variances of the mean from a population that has not been fully characterized and is highly likely to include women with PCOS. Normal values should be determined either by the range of values in a well characterized healthy control popula- tion or by cluster analysis of general population values. 1.2.11 PP Laboratories involved in androgen measurements in females should consider: Determining laboratory normal values by either the range of values in a well character- ized healthy control population or by cluster analysis of the values of a large gen- eral population. Applying the most accurate methods where available. Using extraction/chromatography immunoassays as an alternative to mass spectrome- try only where adequate expertise is available. Future improvements may arise from measurement of 11-oxygenated androgens, and from establishing cut-off levels or thresholds based on large-scale validation in popula- Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 tions of different ages and ethnicities. 1.3 Clinical hyperandrogenism 1.3.1 EBR The presence of hirsutism alone should be considered predictive of biochemical hyperan- ❖❖❖ drogenism and PCOS in adults. 丣 1.3.2 EBR Healthcare professionals could recognize that female pattern hair loss and acne in isola- ❖❖❖ tion (without hirsutism) are relatively weak predictors of biochemical hyperandrogenism. 丣 1.3.3 CR A comprehensive history and physical examination should be completed for symptoms ❖❖❖❖ and signs of clinical hyperandrogenism, including acne, female pattern hair loss and hir- sutism in adults, and severe acne and hirsutism in adolescents. 1.3.4 CR Healthcare professionals should be aware of the potential negative psychosocial impact of ❖❖❖ clinical hyperandrogenism and should consider the reporting of unwanted excess hair growth and/or female pattern hair loss as being important, regardless of apparent clini- cal severity. 1.3.5 CR A modified Ferriman Gallwey score (mFG) of 4 – 6 should be used to detect hirsutism, ❖❖❖❖ depending on ethnicity, acknowledging that self-treatment is common and can limit clini- cal assessment. 1.3.6 CR Healthcare professionals should consider that the severity of hirsutism may vary by eth- ❖❖❖ nicity but the prevalence of hirsutism appears similar across ethnicities. 1.3.7 PP Healthcare professionals should: Be aware that standardized visual scales are preferred when assessing hirsutism, such as the mFG scale in combination with a photographic atlas. Consider the Ludwig or Olsen visual scales for assessing female pattern hair loss. Note that there are no universally accepted visual instruments for assessing the pres- ence of acne. Recognize that women commonly treat clinical hyperandrogenism cosmetically, dimin- ishing their apparent clinical severity. Appreciate that self-assessment of unwanted excess hair growth, and possibly acne and female pattern hair loss, has a high degree of validity and merits close evaluation, even if overt clinical signs of hyperandrogenism are not readily evident on examination. Note that only terminal hairs need to be considered in defining hirsutism, and these can reach >5 mm if untreated, vary in shape and texture, and are generally pigmented. Note that new-onset severe or worsening hyperandrogenism, including hirsutism, requires further investigation to rule out androgen-secreting tumours and ovarian hyperthecosis. Monitor clinical signs of hyperandrogenism, including hirsutism, acne and female pat- tern hair loss, for improvement or treatment adjustment during therapy. 1.4 Ultrasound and polycystic ovarian morphology 1.4.1 EBR Follicle number per ovary (FNPO) should be considered the most effective ultrasound ❖❖❖❖ marker to detect polycystic ovarian morphology (PCOM) in adults. 丣丣 1.4.2 EBR Follicle number per ovary (FNPO), follicle number per cross-section (FNPS) and ovarian vol- ❖❖❖❖ ume (OV) should be considered accurate ultrasound markers for PCOM in adults. 丣丣 1.4.3 CR PCOM criteria should be based on follicle excess (FNPO, FNPS) and/or ovarian ❖❖❖❖ enlargement. 1.4.4 CR Follicle number per ovary (FNPO)  20 in at least one ovary should be considered the ❖❖❖❖ threshold for PCOM in adults. (continued)  International PCOS Guideline 2023 | 1661 Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 1.4.5 CR Ovarian volume (OV)  10 ml or follicle number per section (FNPS)  10 in at least one ❖❖❖❖ ovary in adults should be considered the threshold for PCOM if using older technology or image quality is insufficient to allow for an accurate assessment of follicle counts through- out the entire ovary. 1.4.6 PP There are no definitive criteria to define polycystic ovary morphology (PCOM) on ultra- sound in adolescents, hence it is not recommended in adolescents. 1.4.7 PP When an ultrasound is indicated, if acceptable to the individual, the transvaginal approach is the most accurate for the diagnosis of PCOM. 1.4.8 PP Transabdominal ultrasound should primarily report ovarian volume (OV) with a threshold of  10 ml or follicle number per section (FNPS)  10 in either ovary in adults given the dif- ficulty of assessing follicle counts throughout the entire ovary with this approach. 1.4.9 PP In patients with irregular menstrual cycles and hyperandrogenism, an ovarian ultrasound Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 is not necessary for PCOS diagnosis. 1.4.10 PP Thresholds for PCOM should be revised regularly with advancing ultrasound technology, and age-specific cut-off values for PCOM should be defined. 1.4.11 PP There is a need for training in careful and meticulous follicle counting per ovary and clear standardized protocols are recommended for PCOM reporting on ultrasound including at a minimum: Last menstrual period (or stage of cycle). Transducer bandwidth frequency. Approach/route assessed. Total number of 2–9 mm follicles per ovary. Measurements in three dimensions (in cm) or volume of each ovary. Other ovarian features and/or pathology including ovarian cysts, corpus lutea, domi- nant follicles (10 mm) (which should not be included in ovarian volume calculations). Reliance on the contralateral ovary FNPO for diagnosis of PCOM, where a dominant folli- cle is noted. Uterine features and/or pathology including endometrial thickness and pattern. 1.5 € llerian Hormone in the diagnosis of PCOS Anti-Mu 1.5.1 EBR € llerian hormone (AMH) could be used for defining PCOM in adults. Serum anti-Mu ❖❖❖ 丣丣丣 1.5.2 EBR Serum AMH should only be used in accordance with the diagnostic algorithm, noting that ❖❖❖❖ in patients with irregular menstrual cycles and hyperandrogenism, an AMH level is not 丣丣丣 necessary for PCOS diagnosis. 1.5.3 EBR We recommend that serum AMH should not be used as a single test for the diagnosis ❖❖❖❖ of PCOS. 丣丣丣 1.5.4 EBR Serum AMH should not yet be used in adolescents. ❖❖❖❖ 丣丣丣 1.5.5 PP Either serum AMH or ultrasound may be used to define PCOM; however, both tests should not be performed to limit overdiagnosis. 1.5.6 PP Laboratories and healthcare professionals need to be aware of factors that influence AMH in the general population including: Age: Serum AMH generally peaks between the ages of 20–25 years in the gen- eral population. Body mass index (BMI): Serum AMH is lower in those with higher BMI in the gen- eral population. Hormonal contraception and ovarian surgery: Serum AMH may be suppressed by cur- rent or recent COCP use. Menstrual cycle day: Serum AMH may vary across the menstrual cycle. 1.5.7 PP Laboratories involved in AMH measurements in females should use population and assay specific cut-offs. 1.6 Ethnic variation 1.6.1 EBR Healthcare professionals should be aware of the high prevalence of PCOS in all ethnicities ❖❖❖❖ and across world regions, ranging from 10–13% globally using the Rotterdam criteria. 丣丣 1.6.2 EBR Healthcare professionals should be aware that PCOS prevalence is broadly similar across ❖❖❖❖ world regions, but may be higher in South East Asian and Eastern Mediterranean regions. 丣丣 (continued) 1662 | Teede et al. Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 1.6.3 PP Healthcare professionals should be aware that the presentation of PCOS may vary across ethnic groups. 1.7 Menopause life stage 1.7.1 CR A diagnosis of PCOS could be considered as enduring / lifelong. ❖❖❖ 1.7.2 CR Healthcare professionals could consider that both clinical and biochemical hyperandro- ❖❖❖ genism persist in the postmenopause for women with PCOS. 1.7.3 CR PCOS diagnosis could be considered postmenopause if there is a past diagnosis, or a long- ❖❖❖ term history of oligo-amenorrhoea with hyperandrogenism and/or PCOM, during the ear- lier reproductive years (age 20–40). 1.7.4 CR Further investigations should be considered to rule out androgen-secreting tumours and ❖❖❖ ovarian hyperthecosis in postmenopausal women presenting with new-onset, severe or Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 worsening hyperandrogenism including hirsutism. 1.8 Cardiovascular disease risk 1.8.1 EBR Women with PCOS should be considered at increased risk of cardiovascular disease and ❖❖❖ potentially of cardiovascular mortality, acknowledging that the overall risk of cardiovascu- 丣 lar disease in pre-menopausal women is low. 1.8.2 EBR All women with PCOS should be assessed for cardiovascular disease risk factors. ❖❖❖❖ 丣 1.8.3 CR All women with PCOS, regardless of age and BMI, should have a lipid profile (cholesterol, ❖❖❖❖ low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride level) at diagnosis. Thereafter, frequency of measurement should be based on the presence of hyperlipidaemia and additional risk factors or global cardiovascular risk. 1.8.4 CR All women with PCOS should have blood pressure measured annually and when planning ❖❖❖❖ pregnancy or seeking fertility treatment, given the high risk of hypertensive disorders in pregnancy and the associated comorbidities. 1.8.5 CR Funding bodies should recognize that PCOS is highly prevalent with multisystem effects ❖❖❖❖ including cardiometabolic disease and should diversify and increase research support accordingly. 1.8.6 CR Cardiovascular general population guidelines could consider the inclusion of PCOS as a ❖❖❖ cardiovascular risk factor. 1.8.7 CR Healthcare professionals, women with PCOS and other stakeholders should all prioritize ❖❖❖❖ preventative strategies to reduce cardiovascular risk. 1.8.8 PP Consideration should be given to the differences in cardiovascular risk factors, and cardio- vascular disease, across ethnicities (see 1.6.1) and age, when determining frequency of risk assessment. 1.9 Impaired glucose tolerance and type 2 diabetes risk 1.9.1 EBR Healthcare professionals and women with PCOS should be aware that, regardless of age ❖❖❖❖ and BMI, women with PCOS have an increased risk of impaired fasting glucose, impaired 丣丣 glucose tolerance and type 2 diabetes. 1.9.2 EBR Glycaemic status should be assessed at diagnosis in all adults and adolescents with PCOS. ❖❖❖❖ 丣丣 1.9.3 CR Glycaemic status should be reassessed every one to three years, based on additional indi- ❖❖❖❖ vidual risk factors for diabetes. 1.9.4 CR Healthcare professionals, women with PCOS and other stakeholders should prioritize pre- ❖❖❖❖ ventative strategies to reduce type 2 diabetes risk. 1.9.5 CR Funding bodies should recognize that PCOS is highly prevalent, has significantly higher ❖❖❖❖ risk for diabetes, and should be funded accordingly. 1.9.6 CR Diabetes general population guidelines should consider the inclusion of PCOS as an inde- ❖❖❖❖ pendent risk factor for diabetes. 1.9.7 PP Healthcare professionals, adults and adolescents with PCOS and their first-degree rela- tives, should be aware of the increased risk of diabetes and the need for regular glycae- mic assessment. 1.9.8 PP Women with type 1 and type 2 diabetes have an increased risk of PCOS and screening should be considered in individuals with diabetes. (continued)  International PCOS Guideline 2023 | 1663 Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY Glycaemic testing 1.9.9 EBR Healthcare professionals and women with PCOS should recommend the 75-g oral glucose ❖❖❖❖ tolerance test (OGTT) as the most accurate test to assess glycaemic status in PCOS, regard- 丣 less of BMI. 1.9.10 EBR If an OGTT cannot be performed, fasting plasma glucose and/or glycated haemoglobin ❖❖❖ (HbA1c) could be considered, noting significantly reduced accuracy. 丣 1.9.11 EBR An OGTT should be considered in all women with PCOS and without pre-existing diabetes, ❖❖❖ when planning pregnancy or seeking fertility treatment, given the high risk of hyperglycae- 丣 mia and the associated comorbidities in pregnancy. If not performed preconception, an OGTT could be offered at the first prenatal visit and all women with PCOS should be of- fered the test at 24–28 weeks gestation. 1.9.12 PP Insulin resistance is a pathophysiological factor in PCOS, however, clinically available in- Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 sulin assays are of limited clinical relevance and are not recommended in routine care (re- fer to 3.1.10). 1.10 Obstructive Sleep Apnea 1.10.1 EBR Healthcare professionals should be aware that women with PCOS have significantly higher ❖❖❖❖ prevalence of obstructive sleep apnea compared to women without PCOS, independent 丣丣丣 of BMI. 1.10.2 EBR Women with PCOS should be assessed for symptoms of obstructive sleep apnea (i.e., snor- ❖❖❖❖ ing in combination with waking unrefreshed from sleep, daytime sleepiness or fatigue) 丣丣丣 and if present, screen with validated tools or refer for assessment. 1.10.3 PP Simple obstructive sleep apnea screening questionnaires (such as the Berlin questionnaire, validated in the general population) can assist in identifying obstructive sleep apnea in women with PCOS, noting that diagnosis requires a formal sleep study. 1.10.4 PP Goals of treatment should target obstructive sleep apnea related symptom burden. 1.11 Endometrial hyperplasia and cancer 1.11.1 EBR Healthcare professionals should be aware that premenopausal women with PCOS have ❖❖❖❖ markedly higher risk of developing endometrial hyperplasia and endometrial cancer. 丣 1.11.2 PP Women with PCOS should be informed about the increased risk of endometrial hyperpla- sia and endometrial cancer, acknowledging that the overall chance of developing endome- trial cancer is low, therefore routine screening is not recommended. 1.11.3 PP Long-standing untreated amenorrhea, higher weight, type 2 diabetes and persistent thick- ened endometrium are additional to PCOS as risk factors for endometrial hyperplasia and endometrial cancer. 1.11.4 PP Women with PCOS should be informed of preventative strategies including weight man- agement, cycle regulation and regular progestogen therapy. 1.11.5 PP When excessive endometrial thickness is detected, consideration of a biopsy with histolog- ical analysis and withdrawal bleed is indicated. 1.12 Risks in first degree relatives 1.12.1 EBR Healthcare professionals could consider that fathers and brothers of women with PCOS ❖❖❖ may have an increased prevalence of metabolic syndrome, type 2 diabetes, and 丣 hypertension. 1.12.2 PP The cardiometabolic risk in female first degree relatives of women with PCOS remains inconclusive. 2 Prevalence, screening and management of psychological features and models of care General principles PP Psychological features are common and important components of PCOS that all health- care professionals should be aware of. PP Funding bodies should recognize that PCOS is highly prevalent, and has significantly higher psychological disorders which should be prioritized and funded accordingly. 2.1 Quality of Life 2.1.1 EBR Healthcare professionals and women should recognize the adverse impact of PCOS and/or ❖❖❖❖ PCOS features on quality of life in adults. 丣丣 (continued) 1664 | Teede et al. Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 2.1.2 PP Women with PCOS should be asked about their perception of PCOS related-symptoms, im- pact on quality of life, key concerns, and priorities for management. 2.2 Depression and Anxiety 2.2.1 EBR Healthcare professionals should be aware of the high prevalence of moderate to severe de- ❖❖❖❖ pressive symptoms and depression in adults and adolescents with PCOS and should screen 丣丣丣丣 for depression in all adults and adolescents with PCOS, using regionally validated screen- ing tools. 2.2.2 EBR Healthcare professionals should be aware of the high prevalence of moderate to severe ❖❖❖❖ anxiety symptoms and anxiety disorders in adults and should screen for anxiety in all 丣丣丣丣 adults with PCOS, using regionally validated screening tools. 2.2.3 CR If moderate or severe depressive or anxiety symptoms are detected, practitioners should ❖❖❖❖ further assess, refer appropriately, or offer treatment. Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 2.2.4 PP Severity of symptoms and clinical diagnosis of depression or anxiety should guide management. The optimal interval for anxiety and depression screening is not known. A pragmatic ap- proach could include screening at diagnosis with repeat screening based on clinical judge- ment, risk factors, comorbidities, and life events, including the perinatal period. Screening for mental health disorders comprises assessment of risk factors, symptoms, and risk of self-harm and suicidal intent. 2.3 Psychosexual function 2.3.1 CR Healthcare professionals could consider the multiple factors that can influence psychosex- ❖❖❖ ual function in PCOS including higher weight, hirsutism, mood disorders, infertility and PCOS medications. 2.3.2 CR Permission to discuss psychosexual function should be sought noting that the diagnosis of ❖❖❖❖ psychosexual dysfunction requires both low psychosexual function combined with re- lated distress. 2.4 Body Image 2.4.1 EBR Healthcare professionals should be aware that features of PCOS can have a negative im- ❖❖❖❖ pact on body image. 丣丣 2.5 Eating disorders 2.5.1 EBR Eating disorders and disordered eating should be considered in PCOS, regardless of weight, ❖❖❖ especially in the context of weight management and lifestyle interventions (see sections 丣丣 2.4 and 3.6). 2.5.2 PP If disordered eating or eating disorders are suspected, appropriately qualified practitioners should further assess via a full diagnostic interview. If an eating disorder or disordered eating is detected, appropriate management and sup- port should be offered. 2.6 Information resources, models of care, cultural and linguistic considerations 2.6.1 Information needs 2.6.1.1 EBR Tailored information, education and resources that are high-quality, culturally appropri- ❖❖❖❖ ate and inclusive should be provided to all with PCOS. 丣丣丣 2.6.1.2 EBR Information, education and resources are a high priority for patients with PCOS and should ❖❖❖❖ be provided in a respectful and empathic manner. 丣丣丣 2.6.1.3 CR Entities responsible for healthcare professional education should ensure that information ❖❖❖❖ and education on PCOS is systemically embedded at all levels of healthcare professional training to address knowledge gaps. 2.6.1.4 PP The diversity of the population should be considered when adapting practice paradigms. Healthcare professional education opportunities should be optimised at all stages of grad- uate and postgraduate training and continuing professional development and in practice support resources. 2.6.1.5 PP Women should be counselled on the risk of misinformation and guided to evidence- based resources. 2.6.2 Models of care 2.6.2.1 CR Models of care should prioritize equitable access to evidence-based primary care with ❖❖❖❖ pathways for escalation to integrated specialist and multidisciplinary services as required. (continued)  International PCOS Guideline 2023 | 1665 Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 2.6.2.2 PP Strategies to deliver optimal models of care could include healthcare professional educa- tion, care pathways, virtual care, broader health professional engagement (e.g., nurse prac- titioners) and coordination tools. 2.6.3 Support to manage PCOS 2.6.3.1 CR Public health actors should consider increasing societal awareness and education on PCOS ❖❖❖ to reduce stigma and marginalization. 2.6.3.2 PP Culturally appropriate resources and education on PCOS across the life span for families of those with the condition should be considered. 2.6.4 Patient care 2.6.4.1 EBR Healthcare professionals should employ shared decision-making and support patient ❖❖❖❖ agency or ability to take independent actions to manage their health and care. 丣丣丣 Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 2.6.4.2 EBR The importance of being knowledgeable about PCOS, of applying evidence-based practices ❖❖❖❖ when sharing news on diagnosis, treatment, and health implications, and of ascertaining 丣丣丣 and focusing on patient priorities, should be recognized. 2.6.4.3 CR Healthcare system leaders should enable system wide changes to support healthcare pro- ❖❖❖❖ fessional training, knowledge and practice in sharing news optimally, shared decision making and patient agency, including ensuring adequate consultation time and accessi- ble resources. 2.6.4.4 PP Evidence-based strategies for shared decision making and for sharing news (such as the SPIKES framework) are readily available and should be used to inform PCOS care. All healthcare professionals partnering with women with PCOS should be knowledgeable in sharing news, in shared decision-making, and in supporting patient self-management. Evidence-based strategies and resources can be used to support patient activation, which refers to modifiable knowledge, skills, ability, confidence, and willingness to self-manage one’s own health and care. 2.7 Psychological therapy 2.7.1 CR Women with PCOS diagnosed with depression, anxiety, and/or eating disorders should be ❖❖❖❖ offered psychological therapy guided by regional general population guidelines and the preference of the woman with PCOS. 2.7.2 CR Women with PCOS with disordered eating, body image distress, low self-esteem, problems ❖❖❖❖ with feminine identity, or psychosexual dysfunction should be offered evidence-based treatments (e.g., cognitive behaviour therapy) where appropriate. 2.8 Antidepressant and anxiolytic treatment 2.8.1 CR Psychological therapy could be considered first-line management, and antidepressant ❖❖❖ medications considered in adults where mental health disorders are clearly documented and persistent, or if suicidal symptoms are present, based on general popula- tion guidelines. 2.8.2 PP Lifestyle intervention and other therapies (e.g., COCP, metformin, laser hair removal) that target PCOS features should be considered, given their potential to improve psychological symptoms. Where pharmacological treatment for anxiety and depression is offered in PCOS, health- care professionals should apply caution: to avoid inappropriate treatment with antidepressants or anxiolytics. to limit use of agents that exacerbate PCOS symptoms, including weight gain. Healthcare professionals should be aware that not managing anxiety and depression may impact adherence to PCOS treatment / management. 3 Lifestyle management 3.1 Effectiveness of lifestyle interventions 3.1.1 EBR Lifestyle intervention (exercise alone or multicomponent diet combined with exercise and ❖❖❖❖ behavioural strategies) should be recommended for all women with PCOS, for improving 丣 metabolic health including central adiposity and lipid profile. 3.1.2 CR Healthy lifestyle behaviours encompassing healthy eating and/or physical activity should ❖❖❖❖ be recommended in all women with PCOS to optimize general health, quality of life, body composition and weight management (maintaining weight, preventing weight gain and/or modest weight loss). (continued) 1666 | Teede et al. Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 3.1.3 PP Healthcare professionals should be aware that lifestyle management is a core focus in PCOS management. 3.1.4 PP Lifestyle management goals and priorities should be co-developed in partnership with women with PCOS, and value women’s individualized preferences. 3.1.5 PP There are benefits to a healthy lifestyle even in the absence of weight loss. 3.1.6 PP In those with higher weight, weight management can be associated with significant clinical improvements and the following key points need to be considered including: A lifelong focus on prevention of further weight gain. If the goal is to achieve weight loss, a tailored energy deficit could be prescribed for women, considering individual energy requirements, body weight and physical activ- ity levels. The value of improvement in central adiposity (e.g., waist circumference, waist-hip ra- Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 tio) or metabolic health. The need for ongoing assessment and support. 3.1.7 PP Healthcare professionals should be aware of weight stigma when discussing lifestyle man- agement with women with PCOS (see 3.6). 3.1.8 PP Healthy lifestyle and optimal weight management, in the context of structured, intensive, and ongoing clinical support, appears equally effective in PCOS as in the gen- eral population. 3.1.9 PP In those who are not overweight, in the adolescent and at key life points, the focus should be on healthy lifestyle and the prevention of excess weight gain. 3.1.10 PP Insulin resistance is a pathophysiological factor in PCOS, however, clinically available in- sulin assays are of limited clinical relevance and should not be used in routine care (refer to 1.9.12). 3.2 Behavioural Strategies 3.2.1 CR Lifestyle interventions could include behavioural strategies such as goal-setting, self-mon- ❖❖❖ itoring, problem solving, assertiveness training, reinforcing changes, and relapse preven- tion, to optimize weight management, healthy lifestyle and emotional wellbeing in women with PCOS. 3.2.2 PP Behavioural support could include: goal-setting, problem solving, self-monitoring and reviewing, or SMART goals (Specific, Measurable, Achievable, Realistic and Timely). 3.2.3 PP Comprehensive healthy behavioural or cognitive behavioural interventions could be con- sidered to increase support, engagement, retention, adherence, and maintenance of healthy lifestyle and improve health outcomes in women with PCOS. 3.3 Dietary Intervention 3.3.1 EBR Healthcare professionals and women should consider that there is no evidence to support ❖❖❖ any one type of diet composition over another for anthropometric, metabolic, hormonal, 丣 reproductive or psychological outcomes. 3.3.2 CR Any diet composition consistent with population guidelines for healthy eating will have ❖❖❖❖ health benefits and, within this, healthcare professionals should advise sustainable healthy eating tailored to individual preferences and goals. 3.3.3 PP Tailoring of dietary changes to food preferences, allowing for a flexible, individual and co-developed approach to achieving nutritional goals, and avoiding unduly restrictive and nutritionally unbalanced diets, are important, as per general popula- tion guidelines. 3.3.4 PP Barriers and facilitators to optimize engagement and adherence to dietary change should be discussed, including psychological factors, physical limitations, socioeconomic and so- ciocultural factors, as well as personal motivators for change. The value of broader family engagement should be considered. Referral to suitably trained allied healthcare professio- nals needs to be considered when women with PCOS need support with optimizing their diet. 3.4 Exercise Intervention 3.4.1 EBR Healthcare professionals and women could consider that there is a lack of evidence sup- ❖❖❖ porting any one type and intensity of exercise being better than another for anthropomet- 丣 ric, metabolic, hormonal, reproductive or psychological outcomes. (continued)  International PCOS Guideline 2023 | 1667 Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 3.4.2 CR Any physical activity consistent with population guidelines will have health benefits and, ❖❖❖❖ within this, healthcare professionals should advise sustainable physical activity based on individual preferences and goals. 3.4.3 CR Healthcare professionals should encourage and advise the following in concordance with ❖❖❖❖ general population physical activity guidelines: All adults should undertake physical activity as doing some physical activity is better than none. Adults should limit the amount of time spent being sedentary (e.g., sitting, screen time) as replacing sedentary time with physical activity of any intensity (including light intensity) provides health benefits. For the prevention of weight gain and maintenance of health, adults (18–64 years) should aim for a minimum of 150 to 300 minutes of moderate intensity activities or 75 to 150 minutes of vigorous intensity aerobic activity per week or an equivalent combination of both spread throughout the week, plus muscle strengthening activities Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 (e.g., resistance/flexibility) on two non-consecutive days per week. For promotion of greater health benefits including modest weight-loss and prevention of weight-regain, adults (18–64 years) should aim for a minimum of 250 min/week of moderate intensity activities or 150 min/week of vigorous intensities or an equivalent combination of both, plus muscle strengthening activities (e.g., resistance/flexibility) ideally on two non-consecutive days per week. Adolescents should aim for at least 60 minutes of moderate- to vigorous-intensity phys- ical activity per day, including activities that strengthen muscle and bone at least three times per week. 3.4.4 PP Physical activity is any bodily movement produced by skeletal muscles that requires energy expenditure. It includes leisure time physical activity, transportation (e.g., walking or cycling), occupational (i.e., work), household chores, playing games, sports or planned exercise, or activities in the context of daily, family and commu- nity activities. 3.4.5 PP Aerobic activity is best performed in bouts of at least 10 minutes duration, aiming to achieve at least 30 minutes daily on most days. 3.4.6 PP Barriers and facilitators to optimize engagement and adherence to physical activity should be discussed, including psychological factors (e.g., body image concerns, fear of injury, fear of failure, mental health), personal safety concerns, environmental factors, physical limi- tations, socioeconomic factors, sociocultural factors, and personal motivators for change. The value of broader family engagement should be considered. Referral to suitably trained allied healthcare professionals needs to be considered for optimizing physical activity in women with PCOS. 3.4.7 PP Self-monitoring, including with fitness tracking devices and technologies for step count and exercise intensity, could be considered as an adjunct to support and promote active lifestyles and minimize sedentary behaviours. 3.5 Factors affecting weight gain in PCOS 3.5.1 EBR Healthcare professionals and women with PCOS could consider that there is a lack of con- ❖❖❖ sistent evidence of physiological or behavioural lifestyle differences, related to weight, in 丣 women with PCOS compared to women without PCOS. 3.5.2 PP Whilst the specific mechanisms are unclear, it is recognized that many women with PCOS will have underlying mechanisms that drive greater longitudinal weight gain and higher BMI which may: Underpin greater challenges with weight management. Highlight the importance of lifelong healthy lifestyle strategies and prevention of excess weight gain. Assist women with PCOS and healthcare professionals in forming realistic, tailored life- style goals. 3.6 Weight Stigma 3.6.1 EBR Many women with PCOS experience weight stigma in healthcare and other settings and ❖❖❖❖ the negative biopsychosocial impacts of this should be recognized. 丣丣 3.6.2 CR Healthcare professionals should be aware of their weight biases and the impact this has ❖❖❖❖ on their professional practice and on women with PCOS. 3.6.3 CR Health policy makers, managers and educators should promote awareness of weight ❖❖❖❖ stigma and invest in weight stigma education and minimization strategies. (continued) 1668 | Teede et al. Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY 3.6.4 PP Healthcare professionals should be aware of weight-inclusive practices which promote ac- ceptance of and respect for body size diversity and focus on improvement of health behav- iours and health outcomes for people of all sizes. In PCOS this includes: Acknowledging that whilst higher weight is a risk factor for PCOS and its complications, it is only one indicator of health and broader factors should be assessed. Asking permission to discuss and measure weight and using strategies to minimize dis- comfort (e.g., blind weighing). Recognizing that the terms “overweight” and “obese/obesity” can be stigmatizing with suggested alternatives including “higher weight”. If weighing, explaining how weight information will be used to inform risks, prevention and treatment and how not knowing may impact on recommendations. Ensuring appropriate equipment is available for women of all sizes. Offering options of weight-centric care (promoting intentional weight loss) or weight-in- clusive care (promoting healthy lifestyle change without focusing on intentional weight loss) tailored to individual goals and preferences. Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 Offering all women best practice assessment, treatment and support regardless of weight, acknowledging that weight may be a non-modifiable risk factor when using life- style modification alone. 3.6.5 PP Increasing awareness of weight stigma among family members of women and adolescents with PCOS should be considered. 4 Management of non-fertility features 4.1 Pharmacology treatment principles in PCOS PP Shared decision making between the patient (and parent/s or guardian/s, if the patient is a child) and the healthcare professional is required. PP An individual’s characteristics, preferences and values must be elicited and considered when recommending any intervention alone or in combination. PP Understanding how individual adults and adolescents value treatment outcomes is essen- tial when prescribing medications. PP Medical therapy is generally not approved for use specifically in PCOS and recommended use is therefore evidence-based, but off-label. Healthcare professionals need to inform adults, adolescents and their parents/s or guardian/s and discuss the evidence, possible concerns and side effects. Regulatory agencies should consider approval of evidence-based medications for use in PCOS. 4.2 Combined Oral Contraceptive Pills 4.2.1 EBR Combined oral contraceptive pills (COCP) could be recommended in reproductive age ❖❖❖ adults with PCOS for management of hirsutism and/or irregular menstrual cycles. 丣 4.2.2 EBR The COCP could be considered in adolescents at risk or with a clear diagnosis of PCOS for ❖❖❖ management of hirsutism and/or irregular menstrual cycles. 丣 4.2.3 EBR Healthcare professionals could consider that there is no clinical advantage of using high ❖❖❖ dose ethinylestradiol ( 30 μg) versus low dose ethinylestradiol (< 30 μg) when treating hir- 丣 sutism in adults with PCOS. 4.2.4 EBR General population guidelines should be considered when prescribing COCP in adults and ❖❖❖ adolescents with PCOS as specific types or doses of progestins, estrogens or combinations 丣 of COCP cannot currently be recommended. 4.2.5 EBR The 35μg ethinyl estradiol plus cyproterone acetate preparations should be considered as ❖❖❖ second-line therapy, versus other COCPs, balancing benefits and adverse effects, including 丣 venous thromboembolic risks. 4.2.6 EBR Progestin only oral contraceptives may be considered for endometrial protection, based on ❖❖❖ general population guidelines, acknowledging that evidence in women with PCOS 丣 is limited. 4.2.7 PP When prescribing COCPs in adults and adolescents with PCOS, and adolescents at risk of PCOS It is important to address main presenting symptoms and consider other treatments such as cosmetic therapies. Shared decision-making (including accurate information and reassurance on the effi- cacy and safety of COCP) is recommended and likely to improve adherence. Natural estrogen preparations and the lowest effective estrogen doses (such as 20–30 μg of ethinyl estradiol or equivalent), need consideration, balancing efficacy, metabolic risk profile, side effects, cost, and availability. (continued)  International PCOS Guideline 2023 | 1669 Table 4. Continued NO. TYPE RECOMMENDATION GRADE/QUAITY The relatively limited evidence on COCPs specifically in PCOS needs to be appreciated with practice informed by general population guidelines. The relative and absolute contraindications and side effects of COCPs need to be consid- ered and be the subject of individualized discussion. PCOS specific features, such as higher weight and cardiovascular risk factors, need to be considered. 4.3 Metformin 4.3.1 EBR Metformin alone should be considered in adults with PCOS and a BMI  25 kg/m2 for an- ❖❖❖ thropometric, and metabolic outcomes including insulin resistance, glucose, and 丣 lipid profiles. 4.3.2 EBR Metformin alone could be considered in adolescents at risk of or with PCOS for cycle regu- ❖❖❖ lation, acknowledging limited evidence. 丣 Downloaded from https://academic.oup.com/humrep/article/38/9/1655/7241786 by guest on 06 June 2024 4.3.3 CR Metformin alone may be considered in adults with PCOS and BMI < 25 kg/m2, acknowledg- ❖❖❖ ing limited evidence. 4.3.4 PP Where metformin is prescribed the following need to be considered: Shared decision making needs to consider feasibility and effectiveness of active lifestyle intervention. Women should be informed that metformin and active lifestyle interven- tion have similar efficacy. Mild adverse effects, including gastrointestinal side-effects are generally dose depen- dent and self-limiting. Starting at a low dose, with 500 mg increments 1–2 weekly and extended-release prepa- rations may minimize side effects and improve adherence. Suggested maximum daily dose is 2.5 g in adults and 2g in adolescents. Use appears safe long-term, based on use in other populations, however indications for ongoing requirement needs to be considered. Use may be associated with low vitamin B12 levels, especially in those with risk factors for low vitamin B12 (e.g., diabetes, post bariatric / metabolic surgery, pernicious anae- mia, vegan diet etc.), where monitoring should be considered. 4.4 Metformin and combined oral contraceptive pills 4.4.1 EBR COCP could be used over metformin for management of hirsutism in irregular menstrual ❖❖❖ cycles in PCOS. 丣 4.4.2 EBR Metformin could be used over COCP for metabolic indications in PCOS. ❖❖❖ 丣 4.4.3 EBR The combination of COCP and metformin could be considered to offer little additional clin- ❖❖❖ ical benefit over COCP or metformin alone, in adults with PCOS with a BMI  30 kg/m2. 丣 4.4.4. PP In combination with the COCP, metformin may be most beneficial in high metabolic risk groups including those with a BMI >30 kg/m2, diabetes risk factors, impaired glucose toler- ance or high-risk ethnic groups. 4.4.5 PP Where COCP is contraindicated, not accepted or not tolerated, metformin may be consid- ered for irregular menstrual cycles. For hirsutism, other interventions may be needed. 4.5 Anti-obesity pharmacological agents 4.5.1 CR Anti-obesity medications including liraglutide, semaglutide, both glucagon-like peptide-1 ❖❖❖ (GLP-1) receptor agonists and orlistat, could be considered, in addition to active lifestyle in- tervention, for the management of higher weight in adults with PCOS as per general popu- lation guidelines. 4.5.2 PP Healthcare professionals should ensure concurrent effective contraception when preg- nancy is possible for women who take GLP-1 receptor agonists, as pregnancy safety data are lacking. 4.5.3 PP Gradual dose escalation for GLP-1 receptor agonists is recommended to reduce gastrointes- tinal adverse effects. 4.5.4 PP Shared decision making, when discussing GLP-1 receptor agonist use with women with PCOS, needs to consider side effects, and the potential need for long-term use in weight management, given the high risk for wei