Scope. Update and expansion of Evidence-based guideline for the assessment and management of PCOS. Clinical context

Transcription

1 Scope Update and expansion of Evidence-based guideline for the assessment and management of PCOS Clinical context Polycystic ovary syndrome (PCOS) is a significant public health issue with reproductive, metabolic and psychological features. PCOS is one of the most common conditions in reproductive aged women affecting 12-21% of reproductive-aged women [1-3] with up to 70% of these affected women with PCOS remaining undiagnosed [3]. In Indigenous 1 women the prevalence is 21% [4]. Presentation can vary across the lifecycle. Women with PCOS can present with a range of features including psychological (poor self-esteem, anxiety, depression) [5-7], reproductive (menstrual irregularity, hirsutism, infertility and pregnancy complications) [8], and metabolic features (insulin resistance (IR), metabolic syndrome, prediabetes, type 2 diabetes (DM2) and cardiovascular risk factors) [9, 10]. Not all women demonstrate all features and there is considerable heterogeneity. Diagnostics and treatments in PCOS remain controversial with: Poorly defined components of PCOS diagnostic criteria; Heterogeneity in the manifestations of the syndrome across the phenotypes; Ethnic differences; Evidence shows that investigation and management by endocrinologists, gynecologists and primary care providers varies widely; These controversies are exacerbated as no common international evidence-based guideline exists that covers all health aspects related to the syndrome. History of Evidence-based guideline for the assessment and management of PCOS In 2008 a national Australian meeting on PCOS, with 25 leaders attending from the research, clinical and community sectors saw the establishment of the independent PCOS Australian Alliance and the mapping of an ambitious plan to improve health outcomes in women with PCOS. The Alliance provides leadership and cohesion to promote education, health and research and support consistent, evidence based, multidisciplinary service provision. This involves cross sector collaborations, community partnerships and interactions with government and policy makers aimed at prevention and management of PCOS within Australia. 1 With acknowledgment that different terms are used, in this context, the word Indigenous refers to all Aboriginal or Torres Straight Islanders.

2 In the absence of any international evidence-based guidelines to inform women and health professionals about PCOS, the PCOS Australian Alliance led, in partnership with consumer advocacy group, the Polycystic Ovary Association of Australia (POSAA) and supported by the non-government organisation, Jean Hailes Foundation for Women s Health, the Evidence-based guideline for the assessment and management of PCOS were developed. The guideline was supported by the Australian Department of Health and Ageing and Health Minister Roxon through funding of the guideline and the subsequent translation program and implementation of a new models of care. Established clinical priorities included: Early diagnosis of PCOS Early detection and treatment of depression, anxiety and mood disorders Early detection and diagnosis of risk factors for pre-diabetes, DM2 and CVD Early detection and treatment of fertility problems and prevention of pregnancy complications. The guideline followed international best practice and integrated the best available evidence with clinical expertise and consumer preferences to provide health professionals, consumers and policy makers with guidance for timely diagnosis, accurate assessment and optimal management of women with PCOS to promote consistency of care and prevention of complications. It was developed using internationally agreed methods for the development of evidence-based guidelines and was approved by the National Health and Medical Research Council (NHMRC). Multidisciplinary committees included a Project Board, PCOS Australian Alliance Strategic Advisory Group and four guideline development groups, comprising experts in PCOS and multiple consumer representatives appointed by the project board and mostly drawn from Alliance members and the consumer advocacy group Polycystic Ovary Association of Australia (POSAA). The guideline contains 38 recommendations, based on the best evidence available up to November 2010, and reflects the identified key clinical priorities and areas of clinical need, covering assessment of PCOS, assessment of emotional wellbeing, management of lifestyle and management of infertility in women with PCOS. The guideline was rated independently using the AGREE tool and received a score of 6 and 6-7 by two independent reviewers, with a highest possible score of 7. The work of the guideline resulted in various publications including a summary in the Medical Journal of Australia [11], a discussion of the methods [12], multiple systematic reviews [13-17] and publications related to translation [18-21]. The US National Institute of Health (NIH) commended the evidence-based guideline and translation model developed by the PCOS Alliance as worthy of imitation ; and the guideline has since been adopted by the National Institute for Health and Care Excellence (NICE) in the UK and under contract, updated in the topic area of infertility with the World Health Organisation (WHO). According to international gold standards and to reflect published evidence, that had potential for significant clinical impact with change in practice, under the auspices of the NHMRC funded PCOS Centre for Research Excellence, the infertility guideline development group was reconvened to consider and incorporate new evidence on the effectiveness of aromatase inhibitors. The systematic search for this section (7.4) captured the evidence up to January The guideline is now due for update and expansion to cover additional aspects of management including IVF, oral contraceptive pill (OCP) and metformin treatment and management of pregnancy in PCOS is needed.

3 Current International guidance To date, no international PCOS guideline following best evidence-based principles covering all health aspects related to the syndrome is available. The evidence-based sections of the WHO guideline, developed supported by the Australian team, are aligned with the scope of the Australian guideline, but evidence synthesis was completed in The NICE guideline is limited in scope and is national and not available electronically outside the UK. It too is based largely on the Australian guideline. Current professional society statements are limited in scope, do not follow the AGREEII process, engage broad stakeholders and are often conflicting in recommendations. The US Endocrine clinical practice guideline and European position statements do not follow AGREEII criteria and are expert statements. The American Association of Clinical Endocrinologists recently released a guide to best practice which did not follow systematic evidence synthesis or AGREEII process and again introduces more variation in practice. A recent independent study Systematic evaluation of the quality of clinical practice guidelines on the use of assisted reproductive techniques assessed guidelines based on the AGREEII criteria that addressed ART only. The authors concluded that most were suboptimal and three were deemed Recommended (including the Australian PCOS guideline); nine (64%), were Recommended with modifications ; and two (14%) including international professional society guidelines were Not recommended, highlighting the poor quality of existing guidelines and the major gap in this area [22]. Purpose The purpose of this international evidence-based guideline update and expansion is to integrate the best available evidence with clinical expertise and consumer preferences to provide health professionals, consumers and policy makers with transparent evidence-based guidance on timely diagnosis, accurate assessment and optimal management of women with PCOS and to promote consistency of care and prevention of complications in primary care and specialist settings. Aims These guidelines aim to ensure that women with PCOS receive optimal, evidence-based care, with a focus on prevention of complications. Specifically this work aims to: engage international representation and incorporate International perspectives on PCOS care; prepare a rigorous AGREEII-compliant evidence-based document; include international consumer engagement; develop an international comprehensive guideline for diagnosis, assessment and management of women with PCOS; provide a single source of international evidence-based recommendations to guide clinical practice of women with PCOS and reduce variation in practice worldwide; provide a basis for improving patient outcomes, promoting standardized care and inform the development of standards to assess the clinical practice of healthcare professionals all over the world; develop support tools and resources for education and training of healthcare professionals;

4 implement the evidence-based guideline into practice to drive early diagnosis, risk screening, and appropriate management of this common heterogeneous condition across the lifespan; inform the optimization of healthcare resources and reduction in unnecessary tests; facilitate upskilling and empowerment of patients; promote research and translation into practice and policy. Key principles The key principles that underpin the development and interpretation of all evidence-based guidelines will be adopted: 1. The need for consumers and health professionals to recognise the lifecourse implications of PCOS 2. Health professionals and women need to partner together in managing PCOS and preventing the complications of the condition 3. Consideration should be given to the modulating or exacerbating factors of PCOS 4. When considering therapies, metabolic, reproductive and psychological features of PCOS should be considered 5. Education, optimal lifestyle and emotional wellbeing are critical to therapy at all life stages and with the management of all PCOS features and complications 6. The Indigenous and high risk ethnic population will be considered in developing the guideline. Patient population This guideline is relevant to the assessment and management of adolescents of reproductive age and women who have PCOS, including women with PCOS who are also infertile. Setting and audience These guidelines will apply in all health care settings and to a broad audience, including: Patients Community care practitioners Indigenous health care workers Obstetricians and Gynaecologists Endocrinologists General practitioners/primary care physicians Allied health professionals - Psychologists, Dietitians, Exercise Physiologists, Physiotherapists, Dermatologists Nurses Policy makers Community support groups (ie. POSAA) General public Students

5 Definition of PCOS In the original guideline, The Alliance agreed to adopt the Rotterdam criteria (European Society for Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM)) for diagnosis of PCOS [23]. The Rotterdam criteria are the most accepted diagnostic criteria across Europe, Asia and Australia and were recently endorsed by the National Institutes of Health (NIH) PCOS workshop panel [21]. Rotterdam criteria for diagnosis of PCOS is inclusive of original NIH criteria. Prioritised clinical questions for the Evidence-based guideline for the assessment and management of PCOS Building on our original scope we have now expanded the guideline informed by an International Delphi exercise to determine priorities for PCOS care. Below are the clinical questions to be addressed in the guideline. GDG 1 Screening, diagnostic assessment, risk assessment and life-stage 1. At what time point after onset of menarche do irregular cycles indicate ongoing menstrual dysfunction related to PCOS? 2. In women with suspected PCOS, what is the most effective measure to diagnose PCOS related hyperandrogenism (biochemical)? 3. In women with suspected PCOS, what is the most effective measure to diagnose PCOS related hyperandrogenism (clinical)? 4. What is the most effective ultrasound criteria to diagnose PCOS? 5. Is AMH effective for diagnosis of PCOS? 6. Is AMH effective to diagnosis of PCOM? 7. What is the post-menopausal phenotype of PCOS? 8. Are women with PCOS at increased risk for cardiovascular disease (CVD)? 9. In women with PCOS, what is the most effective tool/method to assess risk of cardiovascular disease (CVD)? 10. Are women with PCOS at increased risk for impaired glucose tolerance, gestational diabetes and type 2 diabetes mellitus? 11. In women with PCOS, what is the most effective tool/method to assess risk of type 2 diabetes mellitus? 12. Are women with PCOS at increased risk for sleep apnea? 13. What is the method/tool most effective to screen for sleep apnea in PCOS? 14. What is the risk of PCOS in relatives of women with PCOS and should they be screened? 15. What is the disease risk in relatives of PCOS (CVD, T2DM)? 16. If time permits: Are all three criteria required to diagnose PCOS in adolescents? GDG 2 - Prevalence, screening, diagnostic assessment and management of emotional wellbeing 17. In women with PCOS: 1) What is the prevalence and severity of reduced QoL? And 2) Should QoL be assessed as part of standard care?

6 18. In women with PCOS, what is the most effective tool/method to screen for symptoms of depression and anxiety? 19. In women with PCOS, what is the most effective tool/method to assess quality of life? 20. Is psychological therapy effective for management and support of depression and/or anxiety, disordered eating, body image distress, self-esteem, feminine identity or psychosexual dysfunction in women with PCOS? 21. Is acupuncture effective for management and support of depression and/or anxiety, disordered eating, body image distress, self-esteem, feminine identity or psychosexual dysfunction in women with PCOS? 22. Are anti-depressants and anxiolytics effective for management and support of depression and/or anxiety or disordered eating in women with PCOS? 23. What is the effectiveness of different models of care compared to usual care? 24. NARRATIVE REVIEW In women with PCOS, what is the most effective tool/method to screen body image distress? 25. NARRATIVE REVIEW In women with PCOS, what is the most effective tool/method to screen disordered eating? 26. NARRATIVE REVIEW In women with PCOS, what is the most effective tool/method to screen psychosexual dysfunction? GDG 3 Lifestyle management and models of care 27. In women with PCOS, are lifestyle interventions (compared to minimal or nothing) effective for anthropometric, metabolic, reproductive, fertility, quality of life and emotional wellbeing outcomes? 28. In women with PCOS, are diet interventions (compared to different diets) effective for improving anthropometric, metabolic, fertility, and emotional wellbeing outcomes? 29. In women with PCOS, are exercise interventions (compared to different exercises) effective for improving anthropometric, metabolic, reproductive, fertility, quality of life and emotional wellbeing outcomes? 30. In women with PCOS, are behavioural interventions (compared to different types of behavioural interventions) effective for improving anthropometric, metabolic, reproductive, fertility, quality of life and emotional wellbeing outcomes? 31. Are women with PCOS at increased risk of obesity? 32. In women with PCOS, does obesity impact on prevalence and severity of hormonal and clinical features? GDG 4 Medical treatment 33. Is the oral contraceptive pill alone or in combination effective for management of hormonal and clinical PCOS features in adolescents and adults with PCOS? 34. Is metformin alone or in combination, effective for management of hormonal and clinical PCOS features and weight in adolescents and adults with PCOS? 35. Are anti-obesity pharmacological agents alone or in combination, effective for management of hormonal and clinical PCOS features and weight in adolescents and adults with PCOS? 36. Are anti-androgen pharmacological agents alone or in combination, effective for management of hormonal and clinical PCOS features and weight in adolescents and adults with PCOS?

7 37. Is inositol alone or in combination with other therapies, effective for management of hormonal and clinical PCOS features and weight in adolescents and adults with PCOS? GDG 5 Screening, diagnostic assessment and management of infertility 38. NARRATIVE REVIEW Should women with PCOS and infertility undergo pre-conception (pre-pregnancy) evaluation (assessment) for (and where possible correction of) risk factors that may adversely affect fertility and response to infertility therapy? 39. NARRATIVE REVIEW Should women with PCOS undergo pre-conception (pre-pregnancy) evaluation (assessment) for (and where possible correction of) risk factors that may lead to adverse (early or late) pregnancy outcomes? 40. NARRATIVE REVIEW Should women with PCOS undergo close (early or late) pregnancy monitoring for adverse pregnancy outcomes? 41. NARRATIVE REVIEW Should women with PCOS and infertility due to anovulation alone with normal semen analysis have tubal patency testing prior to starting ovulation induction with timed intercourse or IUI treatment or delayed tubal patency testing? 42. In women with PCOS, is clomiphene citrate effective for improving fertility outcomes? 43. In women with PCOS, is metformin effective for improving fertility outcomes? 44. In women with PCOS and a BMI<30-32, what is the effectiveness of metformin compared to clomiphene citrate for improving fertility outcomes? 45. In women with PCOS, are aromatase inhibitors effective for improving fertility outcomes? 46. In women with PCOS, are gonadotrophins effective for improving fertility outcomes? 47. In women with PCOS undergoing (controlled) ovarian (hyper) stimulation for IVF/ICSI, does the choice of FSH effect fertility outcomes? 48. In women with PCOS undergoing (controlled) ovarian (hyper) stimulation for IVF/ICSI, is exogenous LH treatment during IVF/ICSI effective for improving fertility outcomes? 49. In women with PCOS, is stimulated IVF/ICSI effective for improving fertility outcomes? 50. In women with PCOS undergoing IVF/ICSI treatment, is the GnRH antagonist protocol or GnRH agonist long protocol the most effective for improving fertility outcomes? 51. In women with PCOS undergoing (controlled) ovarian (hyper) stimulation for IVF/ICSI, is adjuvant metformin effective for improving fertility outcomes? 52. In women with PCOS undergoing GnRH antagonist IVF/ICSI treatment, is the use of hcg trigger or GnRH agonist trigger the most effective for improving fertility outcomes? 53. In women with PCOS, is In Vitro Maturation (IVM) effective for improving fertility outcomes? 54. In women with PCOS, are anti-obesity pharmacological agents effective for improving fertility outcomes? 55. In women with PCOS, is ovarian surgery effective for improving fertility outcomes? 56. In women with PCOS, what is the effectiveness of lifestyle interventions compared to bariatric surgery for improving fertility and adverse outcomes? What the guideline will not address This guideline does not seek to provide full safety and usage information on pharmacological and surgical interventions. It will be specified that the pharmacological and surgical interventions recommended in the

8 guideline should not be applied without consideration to the patient s clinical profile and personal preferences. It will be recommended that the reader consults the Therapeutic Guidelines ( and the National Prescribing Service ( for detailed prescribing information including: indications drug dosage method and route of administration contraindications supervision and monitoring product characteristics adverse effects. This guideline will not include a formal analysis of cost effectiveness of recommended practice versus current/established practice. The clinical and organisational impact of cost on recommendations will be considered in guideline development group meetings. The economic feasibility of the recommendations will not be covered. Governance The guideline process will have a formal international governance process (see figure 1). It be managed by Professor Helena Teede and Robert Norman and their team. ESHRE and ASRM, as the key international partners will provide leadership, enable the multinational process and engage health care personnel as well as provide additional funding and meeting support. ESHRE and ASRM will have representation on the project board, international advisory group and guideline development groups as well as the translation committee to ensure International input by the partnering international society at all stages of guideline development. Other non-funding collaborating societies are being engaged and will be represented on the advisory board and on GDGs. Approvals/ endorsements to be sought Approval/ endorsement can help to promote uptake of guidelines by increasing its credibility and through facilitating dissemination, thus approval of the guideline will be sought from the Australian government NHMRC with endorsement from ESHRE and ASRM, as well as relevant local, national and international guideline development bodies. The NHMRC and EHSRE require developers to follow a robust, prescribed process, which can be arduous and time-intensive, however this has been accounted for in planning tasks and timelines. This process is outlined in the detailed Guideline Protocol (provided on request). Guideline development methods The methods that will be used to develop this guideline are aligned with International best practice, AGREE II criteria and meet the comprehensive criteria of the Australian government NHMRC for approval of evidencebased guidelines and ESHRE. These methods were used in the development of the first evidence-based guideline that was subsequently approved by the NHMRC. The same team of skilled and experienced guideline development methodologists have been assembled for this International update and expanded guideline. Consistent with international best practice, all evidence-based guidelines should consider other available evidence-based guidelines and adapt, update or expand these. As such, GDG members are asked to agree to

9 this process. Additional steps will include the application of the GRADE process. The steps are outlined below in Figure 2 and a detailed guideline development protocol will be available shortly. Funding The development of this guideline is funded through the PCOS Centre for Research Excellence and guideline contributing partners, European Society of Human Reproduction and Embryology [ESHRE] and American Society of Reproductive Medicine [ASRM]. Resources The current Evidence-based guideline for the assessment and management of PCOS, including a summary of recommendations, algorithms, the technical report, guideline development teams, tools and resources can be found at:

10 Figure 1. Governance

11 Figure 2. Guideline development process

12 References 1. Azziz, R., et al., Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. Journal of Clinical Endocrinology & Metababolism, (11): p Diamanti-Kandarakis, E., H. Kandarakis, and R. Legro, The role of genes and environment in the etiology of PCOS. Endocrine, (1): p March, W., et al., The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction, (2): p Davis, S., et al., Preliminary indication of a high prevalence of polycystic ovary syndrome in indigenous Australian women. Gynecological Endocrinology, (6): p Deeks, A., M. Gibson-Helm, and H. Teede, Anxiety and depression in polycystic ovary syndrome: a comprehensive investigation. Fertility & Sterility, (7): p Deeks, A., M. Gibson-Helm, and H. Teede, Is having polycystic ovary syndrome (PCOS) a predictor of poor psychological function including depression and anxiety. Human Reproduction, Advance access published March 23, Moran, L., et al., Polycystic ovary syndrome: a biopsychosocial understanding in young women to improve knowledge and treatment options. Journal of Psychosomatic Obstetrics & Gynecology, (1): p Boomsma, C., et al., A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Human Reproduction Update, (6): p Apridonidze, T., et al., Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism, (4): p Legro, R., et al., Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. Journal of Clinical Endocrinology & Metababolism, (1): p Teede, H.J., et al., Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust, (6): p. S65-S Misso, M. and H. Teede, Evidence based guideline (EBG) development: a practical guide, in Knowledge Transfer: Practices, Types and Challenges, D. Ilic, Editor. 2012, Nova Publishers: New York. 13. Misso, M., et al., Metformin versus clomiphene citrate for infertility in non-obese women with PCOS: a systematic review and meta-analysis. Hum Reprod Update, (1): p Misso, M., et al., Clomiphene citrate and metformin for infertility in PCOS:systematic review. Trends Endocrinol Metab, (10): p Misso, M., et al., Aromatase inhibitors for PCOS: a systematic review and meta-analysis. Human Reprod Update, (3): p Moran, L.J., et al., Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet, (4): p Moran, L.J., et al., Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. Human Reproduction Update, (5): p. 432.

13 18. Costello, M., et al., The treatment of infertility in polycystic ovary syndrome: a brief update. The Australian and New Zealand Journal of Obstetrics and Gynaecology, (4): p Boyle, J., H.J. Teede, and M.L. Misso, Infertility in women with polycystic ovary syndrome and the role of metformin in management. Expert Review of Obstetrics & Gynecology, (6): p Misso, M., et al., Development of evidenced-based guidelines for PCOS and implications for community health. Semin Reprod Med, (3): p NIH Evidence based workshop panel, NIH Evidence based workshop on Polycystic Ovary Syndrome Gutarra-Vilchez, R.B., et al., Systematic evaluation of the quality of clinical practice guidelines on the use of assisted reproductive techniques. Hum Fertil (Camb), (1): p The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome: The Rotterdam ESHRE/ASRM- Sponsered PCOS Consensus Workshop Group. Fertility & Sterility, (1): p