International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2023

Objective: To develop and translate rigorous, comprehensive evidence-based guidelines for diagnosis, assessment and treatment, to improve the lives of those with polycystic ovary syndrome (PCOS) worldwide. Participants: Extensive health professional and consumer or patient engagement informed the guideline priority areas. International society-nominated panels included consumers, and experts in paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, psychology, dietetics, exercise physiology, sleep, bariatric/metabolic surgery, public health, other co-opted experts, project management, evidence synthesis and translation. Evidence: Best practice, evidence-based guideline development involved extensive evidence synthesis and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework covered evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Process: Governance included an international advisory panel, management committee and five guideline development groups with 52 members, consumer and translation committees. The Centre for Research Excellence in Women’s Health in Reproductive Life, funded by the Australian National Health and Medical Research Council (NHMRC), and led by Monash University, partnered with the American Society for Reproductive Medicine, the Endocrine Society, the European Society of Endocrinology and the European Society of Human Reproduction and Embryology. Thirty-six organisations collaborated with international meetings over nine months. Fifty-five prioritised clinical questions involved 52 systematic and three narrative reviews, generating evidence-based and consensus recommendations with accompanying practice points. Committee members nominated by collaborating organisations provided international peer review, and evidence expert-reviewed methods and outputs were submitted to NHMRC for independent review. Recommendations: PCOS

Supported healthy lifestyle remains vital throughout the lifespan in PCOS, with a strong focus on overall health, prevention of weight gain and if required, on weight management.Recognising the benefits if many specific diet and physical activity regimens, there is no one regimen that has benefits over others in PCOS.Weight bias and stigma should be minimised and healthcare professionals should seek permission to weigh women, with explanation of weight-related risks.Combined oral contraceptive pills are first-line pharmacological treatment for menstrual irregularity and hyperandrogenism, with no specific recommended preparation, and a preference for lower dose preparations and those with less side-effects.Metformin is recommended primarily for metabolic features and has greater efficacy than inositol, which offers limited clinical benefits in PCOS.Metformin is not routinely recommended for use in pregnant women with PCOS.Laser therapy is effective for hair reduction in some subgroups, whilst antiandrogens have a limited role, to be used where other therapies are ineffective or are contraindicated.Anti-obesity agents and bariatric/metabolic surgery may be considered based on general population guidelines, balancing potential for benefits and side-effects.
Letrozole is first-line pharmacological infertility therapy, with clomiphene alone or in combination with metformin, gonadotrophins or ovarian surgery having a role as second-line therapy.In the absence of an absolute indication for in vitro fertilisation (IVF), women with PCOS and anovulatory infertility could be offered IVF potentially with in vitro maturation, as third-line therapy where other ovulation induction therapies have failed.
Overall, evidence in PCOS is low to moderate quality.Based on high prevalence and significant health impact, greater priority, funding and research is recommended.Guideline translation will be extensive including multilingual education outputs and evidence-based resources for consumers (the AskPCOS app), healthcare professionals and policy makers.

Context statement on diagnosis: Prelude to the guideline
Here, we build on the 2018 International Evidence-based Guideline for the Assessment, Diagnosis and Management of PCOS, and on the initial consensus-based Rotterdam PCOS diagnostic criteria. 18ere, we progress evidence-based diagnostic criteria and in adults recommend that this requires two of i) clinical/biochemical hyperandrogenism, ii) ovulatory dysfunction or iii) polycystic ovaries on ultrasound and here add elevated anti-mullerian hormone (AMH) levels.We have included the role of AMH in diagnosis in adults but do not recommend AMH or ultrasound in adolescents, due to overlap with normal reproductive physiology.
Exclusion of thyroid disease (thyroid stimulating hormone), hyperprolactinemia (prolactin), and non-classic congenital adrenal hyperplasia (17-hydroxy progesterone) is recommended with further evaluation recommended in those with amenorrhea and more severe clinical features including consideration of hypogonadotropic hypogonadism, Cushing's disease, or suspected androgen producing tumors, noting that overt virilisation is not consistent with PCOS.Clinicians should refer to other relevant guidelines for these diagnoses.
We acknowledge the challenges in defining specific diagnostic features, including around menarche and menopause, where diagnostic features naturally evolve.
The guideline aims to facilitate timely and appropriate diagnosis for women with PCOS, whilst avoiding over diagnosis, especially in adolescents.Specific recommendations of relevance here include: • ultrasound and anti-mullerian (AMH) levels are not recommended in diagnosis in those within 8 years of menarche • young women 'at risk' can be identified, where diagnosis is unclear, with follow-up reassessment • diagnostic features are refined, focused on specificity, to improve diagnostic accuracy.
Resource use in diagnosis will also be reduced with a focus on clinical features in diagnosis, limited indications for ultrasound and AMH as an alternative and with a focus on clinical overt biochemical hyperandrogenism.
We also endorse the recommendation of the National Institutes of Health (NIH) evidence-based methodology workshop of PCOS 2012 that the name of the condition is a distraction and should be changed.We are building on the evidence and guideline efforts with consumer partnership and processes towards a change in the name.
The value and optimal timing of assessment and diagnosis of PCOS should be discussed with the individual patient, considering psychosocial and cultural factors and preferences.Education is vitally important to women at the time of diagnosis, including reassurance about the potential for prevention of complications and about good general reproductive potential and family size, acknowledging some medical assistance may be required.As a general guiding principal, in partnering with women with PCOS in their diagnosis and care, self-empowerment is a priority and personal characteristics, preferences, culture and values should be considered when undertaking assessment, providing information or recommending intervention or treatments.

Interpreting the recommendations
Detailed methods for stakeholder engagement and guideline development can be found in Chapter six: Guideline development methods.In developing and interpreting the guideline, evidence has been evaluated alongside multidisciplinary health professional expertise and consumer perspectives in all stages from conceptualisation, prioritisation, development, review and translation.Variability in resources, health systems and access to healthcare professionals, investigations and therapies was considered across international settings and consistent with best practice, adaptation may be required in translation.Assistance with adaptation can be obtained by contacting helena.teede@monash.edu.
To assist in interpreting guideline recommendations, these are presented by category, terms used, GRADE and quality of evidence.The category of the recommendations includes evidence-based or consensus recommendations and have accompanying relevant practice points as described in Table 1.When sufficient evidence was available in PCOS, an evidence-based recommendation was made, where there was insufficient evidence in PCOS, evidence in general or relevant populations was considered and if appropriate and there was consensus, the GDG made consensus recommendations.Practice points highlight important clinical and implementation issues arising from GDG consideration of evidence-based or consensus recommendations.

CR
Consensus recommendations: In the absence of adequate evidence, a consensus recommendation has been made by the guideline development group, also informed by evidence from the general population.

PP
Practice points: Evidence not sought.A practice point has been made by the guideline development group where important issues arose from discussion of evidence-based or consensus recommendations.
The recommendation terms include 'should', 'could' and 'should not'.These terms are informed by the nature of the recommendation (evidence or consensus), the GRADE framework and evidence quality and are independent descriptors reflecting the judgement of multidisciplinary GDG including consumers.They refer to overall interpretation and practical application of the recommendation, balancing benefits and harms.'Should' is used where benefits of the recommendation exceed harms, and where the recommendation can be trusted to guide practice.Conditional recommendations are reflected using the terms 'could' or 'should/could consider' which are used where either the quality of evidence was limited or the available studies demonstrate little clear advantage of one approach over another, or the balance of benefits to harm was unclear.'Should not' is used where there is either a lack of appropriate evidence, or the harms may outweigh the benefits.
The GRADE of the recommendation is determined by the GDG from structured, transparent consideration of the GRADE framework 16 including desirable effects, undesirable effects, balance of effects, resource requirements and cost effectiveness, equity, acceptability and feasibility and includes: Conditional recommendation against the option Conditional recommendation for either the option or the comparison

Conditional recommendation for the option
Strong recommendation for the option Quality of the evidence is categorised (see Table 2) according to: • information about the number and design of studies addressing the outcome • judgments about the quality of the included studies and/or synthesised evidence, such as risk of bias, inconsistency, indirectness, imprecision and any other considerations that may influence the quality of the evidence • key statistical data • classification of the importance of the outcomes.
The quality of evidence reflects the extent to which our confidence in an estimate of the effect is adequate to support a particular recommendation 16 and was largely determined by the expert evidence synthesis team.

High
Very confident that the true effect lies close to that of the estimate of the effect.

Moderate
Moderate confidence in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is different.

Low
Limited confidence in the effect estimate: The true effect may be substantially different from the estimate of the effect.

Very Low
Very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
GRADE note that quality of evidence is a continuum; any discrete categorisation involves a degree of arbitrariness.Nevertheless, advantages of simplicity, transparency, and vividness outweigh these limitations. 16e recommendations summary in Table 3 below applies the category, descriptive terms, GRADE of the recommendations and the quality of the evidence.Within the body of the guideline, we outline the clinical need for the question, the clinical question, the evidence summary, the recommendation and practice points and a summary of the justification developed by the GDG and modified by extensive international peer review.The comprehensive evidence reviews, profiles and GRADE frameworks supporting each recommendation, can be found in the supplementary Technical Report.
Aligned to Cochrane methods, certainty of evidence varies significantly across outcomes for each clinical question.In this guideline, the recorded evidence certainty reflects the lowest certainty for the top three critical outcomes for each question.Here, evidence was often stronger for the most critical outcome and often high quality randomised controlled trials (RCTs) had addressed an individual question, but consideration of multiple outcomes and inclusion of additional low-quality studies may have resulted in low certainty evidence overall.These nuances in the evidence were considered by the GDG for every clinical question and are outlined in the technical report and GRADE tables.Hence, an apparent discrepancy may be observed between the strength of the recommendation and the certainty of the evidence.Where this occurs, a justification is added to the guideline under the relevant clinical question.
This is a living guideline as outlined in Chapter 6.For the most rapidly progressing areas of the guideline where new evidence is anticipated in the shorter term, an annual scoping review will be completed to search for additional evidence and the process followed as per Chapter 6.In the recommendations table and summary, these are denoted by #.

No. Living # Type Recommendation
Grade/ Quality 1.9.5 CR Funding bodies should recognise 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 independent risk factor for diabetes.
1.9.7 PP Healthcare professionals, adults and adolescents with PCOS and their first-degree relatives, should be aware of the increased risk of diabetes and the need for regular glycaemic 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.

Glycaemic testing
1.9.9 EBR Healthcare professionals and women with PCOS should recommend the 75g oral glucose tolerance test (OGTT) as the most accurate test to assess glycaemic status in PCOS, regardless 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.
1.9.11EBR 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 hyperglycaemia 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 offered the test at 24-28 weeks gestation.
1.9.12PP Insulin resistance is a pathophysiological factor in PCOS, however, clinically available insulin assays are of limited clinical relevance and are not recommended in routine care (refer 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 (OSA) compared to women without PCOS, independent of BMI.

PP
Funding bodies should recognise that PCOS is highly prevalent, has significantly higher psychological disorders which should be prioritised and funded accordingly.

Quality of life
2.1.1EBR Healthcare professionals and women should recognise the adverse impact of PCOS and/or PCOS features on quality of life in adults.

PP
Women with PCOS should be asked about their perception of PCOS related symptoms, impact on quality of life, key concerns and priorities for management.The optimal interval for anxiety and depression screening is not known.A pragmatic approach could include screening at diagnosis with repeat screening based on clinical judgement, risk factors, comorbidities and life events, including the perinatal period.

No
Screening for mental health disorders comprises assessment of risk factors, symptoms, and risk of self-harm and suicidal intent.Where pharmacological treatment for anxiety and depression is offered in PCOS, healthcare professionals should apply caution:

2.3
• 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.

No. Living # Type Recommendation
Grade/ Quality 3 Lifestyle management

Effectiveness of lifestyle interventions
3.1.1EBR Lifestyle intervention (exercise alone or multicomponent diet combined with exercise and behavioural strategies) should be recommended for all women with PCOS, for improving metabolic health including central adiposity and lipid profile.

CR
Healthy lifestyle behaviours encompassing healthy eating and/or physical activity should be recommended in all women with PCOS to optimise general health, quality of life, body composition and weight management (maintaining weight, preventing weight gain and/or modest weight loss).

PP
Healthcare professionals should be aware that lifestyle management is a core focus in PCOS management.

PP
Lifestyle management goals and priorities should be co-developed in partnership with women with PCOS, and value women's individualised preferences.

PP
There are benefits to a healthy lifestyle even in the absence of weight loss.

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 activity levels • the value of improvement in central adiposity (e.g.waist circumference, waist-hip ratio) or metabolic health • the need for ongoing assessment and support.
3.1.7PP Healthcare professionals should be aware of weight stigma when discussing lifestyle management with women with PCOS [see 3.6].
3.1.8PP Healthy lifestyle and optimal weight management, in the context of structured, intensive and ongoing clinical support, appears equally effective in PCOS as in the general population.
3.1.9PP 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.
3.1.10PP Insulin resistance is a pathophysiological factor in PCOS, however, clinically available insulin assays are of limited clinical relevance and should not be used in routine care (refer to 1.9.12).

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, reproductive or psychological outcomes.
3.3.2CR 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.

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 population guidelines.

PP
Barriers and facilitators to optimise engagement and adherence to dietary change should be discussed, including psychological factors, physical limitations, socioeconomic and sociocultural factors, as well as personal motivators for change.
The value of broader family engagement should be considered.Referral to suitably trained allied healthcare professionals needs to be considered when women with PCOS need support with optimising their diet.

Exercise interventions
3.4.1 EBR Healthcare professionals and women could consider that there is a lack of evidence supporting any one type and intensity of exercise being better than another for anthropometric, metabolic, hormonal, reproductive or psychological outcomes.

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.

No. Living # Type Recommendation
Grade/ Quality

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 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 minimise sedentary behaviours.

No. Living # Type Recommendation
Grade/ Quality

Factors affecting weight gain in PCOS
3.5.1 EBR Healthcare professionals and women with PCOS could consider that there is a lack of consistent evidence of physiological or behavioural lifestyle differences, related to weight, in women with PCOS compared to women without PCOS.

PP
Whilst the specific mechanisms are unclear, it is recognised 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 lifestyle goals.

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 recognised.

CR
Healthcare professionals should be aware of their weight biases and the impact this has on their professional practice and on women with PCOS.

CR
Health policy makers, managers and educators should promote awareness of weight stigma and invest in weight stigma education and minimisation strategies.
3.6.4PP Healthcare professionals should be aware of weight-inclusive practices which promote acceptance of and respect for body size diversity and focus on improvement of health behaviours 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 minimise discomfort (e.g.blind weighing) • recognising that the terms 'overweight' and 'obese/obesity' can be stigmatising 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-inclusive care (promoting healthy lifestyle change without focusing on intentional weight loss) tailored to individual goals and preferences • offering all women best practice assessment, treatment and support regardless of weight, acknowledging that weight may be a non-modifiable risk factor when using lifestyle modification alone.
3.6.5PP Increasing awareness of weight stigma among family members of women and adolescents with PCOS should be considered.

No. Living # Type Recommendation
Grade/ Quality 4 Management of non-fertility features

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 essential 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.

Combined oral contraceptive pills
4.2.1 EBR The combined oral contraceptive pill (COCP) could be recommended in reproductive age adults with PCOS for management of hirsutism and/or irregular menstrual cycles.

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.

4.2.3
EBR Health professionals could consider that there is no clinical advantage of using high dose ethinylestradiol (≥ 30 μg) versus low dose ethinylestradiol (< 30 μg) when treating hirsutism 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 of COCP cannot currently be recommended.

4.2.5
EBR 35 μg ethinyl estradiol plus cyproterone acetate preparations should be considered as second-line therapy over other COCPs, balancing benefits and adverse effects, including venous thromboembolic risks.

No. Living # Type Recommendation
Grade/ Quality 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 is limited.

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 efficacy and safety of COCP) is recommended and likely to improve adherence.
• Natural estrogen preparations and the lowest effective estrogen doses (such as 20-30 micrograms of ethinyl estradiol or equivalent), need consideration, balancing efficacy, metabolic risk profile, side-effects, cost and availability. • 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 considered and be the subject of individualised discussion.
• PCOS specific features such as higher weight and cardiovascular risk factors, need to be considered.

4.3.1
EBR Metformin alone should be considered in adults with PCOS and a BMI ≥ 25 kg/m 2 for anthropometric, and metabolic outcomes including insulin resistance, glucose, and lipid profiles.

4.3.2
Metformin alone could be considered in adolescents at risk of or with PCOS for cycle regulation, acknowledging limited evidence.

CR
Metformin alone may be considered in adults with PCOS and BMI < 25 kg/m 2 , acknowledging limited evidence.

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 intervention have similar efficacy.
• Mild adverse effects, including gastrointestinal side-effects are generally dose dependent and self-limiting.

•
Starting at a low dose, with 500 mg increments 1-2 weekly and extended-release preparations may minimise side-effects and improve adherence.
• Suggested maximum daily dose is 2.5 g in adults and 2 g 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 anaemia, vegan diet etc.), where monitoring should be considered.

No. Living # Type Recommendation
Grade/ Quality 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.
4.4.2EBR Metformin could be used over COCP for metabolic indications in PCOS.

EBR
The combination of COCP and metformin could be considered to offer little additional clinical benefit over COCP or metformin alone, in adults with PCOS with a BMI ≤30 kg/m 2 .

PP
In combination with the COCP, metformin may be most beneficial in high metabolic risk groups including those with a BMI > 30 kg/m 2 , diabetes risk factors, impaired glucose tolerance or high-risk ethnic groups.

PP
Where COCP is contraindicated, not accepted or not tolerated, metformin may be considered 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 intervention, for the management of higher weight in adults with PCOS as per general population guidelines.

PP
Healthcare professionals should ensure concurrent effective contraception when pregnancy is possible, for women who take GLP-1 receptor agonists, as pregnancy safety data are lacking.

PP
Gradual dose escalation for GLP-1 receptor agonists is recommended to reduce gastrointestinal adverse effects.
4.5.4PP 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 weight regain after discontinuation, and the lack of long-term safety data.

4.6
Anti-androgen pharmacological agents 4.6.1 EBR In combination with effective contraception, anti-androgens could be considered to treat hirsutism in women with PCOS, if there is a suboptimal response after a minimum of six months of COCP and/or cosmetic therapy.

No. Living # Type Recommendation
Grade/ Quality 4.6.2CR Given the negative psychological impact of female pattern hair loss, anti-androgens in combination with COCP could be trialed, acknowledging the lack of evidence in the PCOS population.
4.6.3PP Whenever pregnancy is possible, healthcare professionals must educate and counsel women and adolescents, parents/s or guardian/s, regarding the risks of incomplete development of external genital structures of male fetuses (undervirilisation) when anti-androgens are used.To prevent this, women who can get pregnant should be strongly counseled to use effective contraception (e.g.intrauterine device or COCPs).
4.6.4PP Anti-androgens could be considered to treat hirsutism, in the presence of another effective form of contraception, for women with contraindications for COCP therapy or when COCPs are poorly tolerated.
4.6.5 PP When prescribing anti-androgens, based on general population recommendations, healthcare professionals should consider that: • spironolactone at 25-100 mg/day appears to have lower risks of adverse effects • cyproterone acetate at doses ≥ 10 mg is not advised due to an increased risk including for meningioma • finesteride has an increased risk of liver toxicity • flutamide and bicalutamide have an increased risk of severe liver toxicity.
The relatively limited evidence on anti-androgens in PCOS needs to be appreciated with small numbers of studies and limited numbers of participants.

PP
Where laser hair removal is prescribed, the following need to be considered: • Wavelength and delivery of laser treatment varies by skin and hair colour.
• Laser is relatively ineffective in women with blond, grey or white hair.

•
The addition of COCP, with or without anti-androgens, to laser treatment may provide greater hair reduction and maintenance compared to laser alone.
Low and high fluence laser appear to have similar efficacy in reducing facial hair, while low fluence laser has reduced associated pain.
4.8.5 PP Mechanical hair removal with Intense Pulse Light (IPL) could be considered, albeit benefits may be less pronounced compared to laser treatment.There is no evidence to support the efficacy of home-based IPL kits.

PP
Policy makers should consider funding this evidence-based effective therapy for women with PCOS to alleviate distressing symptoms of hirsutism, and related negative impact on quality of life, body image and psychological health.

4.9
Bariatric/metabolic surgery 4.9.1 CR Bariatric/metabolic surgery could be considered to improve weight loss, hypertension, diabetes (prevention and treatment), hirsutism, irregular menstrual cycles, ovulation and pregnancy rates in women with PCOS.
4.9.2CR Bariatric/metabolic surgery in women with PCOS should be informed by general population guidelines.
4.9.3CR PCOS is a metabolic condition and could be considered an indication at a lower BMI threshold for bariatric/metabolic surgery similarly to other metabolic conditions including diabetes.

CR
Women should be strongly counseled on the likelihood of rapid return of fertility and the need to commit to effective contraception, ideally prior to surgery.Even when pregnancy is desired, contraception should be continued until a stable weight is achieved, usually after one year, to avoid significantly increased risk of growth restriction, prematurity, small for gestational age, pregnancy complications and prolonged hospitalisation of the infant.

Assessment and treatment of infertility
General principles

PP
All fertility treatment in PCOS should be guided by the fertility management algorithm.

PP
Those with PCOS should be reassured that pregnancy can often be successfully achieved either naturally or with assistance.

PP
Prenatal vitamins supplementation should be commenced with ovulation induction therapy aligned to routine preconception care.

PP
Pregnancy should be excluded prior to ovulation induction therapy.

PP
The use of ovulation induction agents, including letrozole, metformin and clomiphene citrate is off-label in many countries.Where off-label use of ovulation induction agents is allowed, healthcare professionals need to inform women and discuss the evidence, possible concerns and side-effects.

PP
There should be ongoing monitoring of patients for adverse effects and infants for congenital anomalies in all studies conducted with ovulation induction agents and these should be reported in any published papers.

No. Living # Type Recommendation
Grade/ Quality

Preconception risk factors
5.1.1EBR Women with PCOS should be counseled on the adverse impact of excess weight on clinical pregnancy, miscarriage and live birth rates, following infertility treatment.

CR
Consistent with routine preconception care, in women with PCOS planning pregnancy, weight, blood pressure, smoking, alcohol, diet and nutritional status, folate supplementation (higher dose in those with BMI > 30), exercise, sleep and mental, emotional and sexual health should be considered and optimised to improve reproductive and pregnancy outcomes and overall health.

PP
A reproductive life plan and age appropriate education on optimising reproductive health, is recommended in adolescents and women with PCOS, including healthy lifestyle, prevention of excess weight gain, and optimising preconception risk factors.

PP
Healthcare professionals are encouraged to seek permission and if given, to assess weight and body mass index and initiate a dialogue on the importance of weight and lifestyle on women's health before pregnancy.This requires caution to avoid weight stigma and needs to consider the cultural, social and environmental determinants of health (see 3.6).
5.1.5PP Chronic conditions such as diabetes, high blood pressure, anxiety, depression and other mental health conditions, should be optimally managed and women should be counseled regarding the risk of adverse pregnancy outcomes.

CR
In women with PCOS and infertility due to anovulation alone with normal semen analysis, the risks, benefits, costs and timing and techniques of tubal patency testing in relation to the cost and complexity of the treatment, should be considered on an individual basis, depending on personal history and population prevalence, prior to starting ovulation induction with timed intercourse or intrauterine insemination.

EBR
Letrozole should be the first-line pharmacological treatment for ovulation induction in infertile anovulatory women with PCOS, with no other infertility factors.

PP
The use of letrozole is still off-label in many countries.
Where it is not allowed, clinicians should use other ovulation induction agents.

PP
Letrozole should not be given where there is any possibility of a pre-existing pregnancy, though there is no evidence for increased teratogenicity compared to other ovulation induction agents.

No. Living # Type Recommendation
Grade/ Quality 5.4 Clomiphene citrate and metformin 5.4.1 Metformin versus placebo 5.4.1.1EBR Metformin could be used alone, in women with PCOS with anovulatory infertility and no other infertility factors, to improve clinical pregnancy and live birth rates, whilst informing women that there are more effective ovulation agents.

PP
Women should be counseled as to potential mild gastrointestinal side-effects with metformin.
5.4.1.3PP Healthcare and resource burden including monitoring, travel and costs are lower with metformin.
5.4.1.4PP Consideration of age and screening for other fertility factors needs to be discussed before prescribing metformin.

Clomiphene citrate versus metformin
5.4.2.1 EBR Clomiphene citrate could be used in preference to metformin in women with PCOS with anovulatory infertility and no other infertility factors, to improve ovulation, clinical pregnancy and live birth rates.

PP
The risk of multiple pregnancy is increased with clomiphene citrate use (alone or in combination with metformin) and therefore clomiphene cycles may require ultrasound monitoring.

5.4.3
Clomiphene citrate and metformin versus clomiphene citrate alone 5.4.3.1 EBR Clomiphene citrate combined with metformin could be used rather than clomiphene citrate alone in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation and clinical pregnancy rates.

5.4.4
Clomiphene citrate and metformin versus metformin alone 5.4.4.1 EBR Clomiphene citrate combined with metformin could be used rather than metformin alone in women with PCOS with anovulatory infertility and no other infertility factors to improve live birth rates.

PP
Monitoring of combined cycles will need to be equivalent to clomiphene citrate alone.

Clomiphene citrate versus Letrozole
5.4.5.1 EBR Letrozole should be used rather than clomiphene citrate in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, clinical pregnancy, and live birth rates.

PP
Current evidence demonstrates no difference in fetal abnormality rates between letrozole or clomiphene citrate ovulation induction or natural conception.

No. Living # Type Recommendation
Grade/ Quality 5.5 Gonadotrophins 5.5.1 EBR Gonadotrophins alone could be considered rather than clomiphene citrate in therapy naïve women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, clinical pregnancy and live birth rates (refer to PP 5.5.6).
5.5.2EBR Gonadotrophins alone could be used over gonadotrophins combined with clomiphene citrate in women with PCOS who are anovulatory and infertile with clomiphene citrate resistance or failure, and no other infertility factors.
5.5.3EBR Gonadotrophins could be considered rather than the combination of clomiphene citrate and metformin in women with PCOS who are anovulatory and infertile, with clomiphene citrate-resistance and no other infertility factors.
5.5.4EBR Either gonadotrophins or laparoscopic ovarian surgery could be used in women with PCOS who are anovulatory and infertile, with clomiphene citrate-resistance and no other infertility factors, following counselling on higher live birth rate and higher multiple pregnancy rates with gonadotrophins.
5.5.5 EBR Gonadotrophins could be second-line pharmacological therapy for women with PCOS who are anovulatory and infertile, with no other infertility factors and who have failed first-line oral ovulation induction.

PP
Where gonadotrophins are to be prescribed, the following should be considered: • Cost of the intervention for ovulation induction.
• Expertise required for the use of the intervention for ovulation induction.

•
The degree of intensive ultrasound monitoring that is required.
• A low dose step-up gonadotrophin protocol should be used to optimise the chance of monofollicular development.
• Implications of potential multiple pregnancy.

PP
There appears to be no difference in the clinical efficacy of the available gonadotrophin preparations.
5.5.8PP When using gonadotrophins, best clinical practice is to avoid multiple pregnancy.Considerations here include cancelling cycles when there is more than a total of two follicles greater than 14 mm in diameter and advising avoidance of unprotected intercourse.
5.5.9PP Live birth rate, clinical pregnancy rate per patient and ovulation rate per cycle are higher with gonadotrophins than with clomiphene citrate.

PP
A low dose gonadotrophin protocol should be used to optimise the chance of monofollicular growth and minimise multiple pregnancy.
5.5.11PP Cycle monitoring and drug costs coupled with multiple injection will influence choice in gonadotrophin use.

No. Living # Type Recommendation
Grade/ Quality 5.8 Inositol 5.8.1 EBR Inositol in any form alone, or in combination with other therapies, should be considered experimental therapy in women with PCOS with infertility, with benefits and risks currently too uncertain to recommend the use of these agents as fertility therapies.

PP
There is limited evidence with uncertain results, on the effect of inositol on ovulation, clinical pregnancy and live birth rates.
5.8.3 PP Side-effects and safety are not known for inositol.
5.8.4 PP Women need to be aware that these agents can have limited regulation with variable dose, quality, consistency and combination with other agents.
5.8.5 PP Women's personal goals and preferences should be considered when discussing complimentary therapies.

5.9
Anti-obesity pharmacological agents 5.9.1 CR We recommend using anti-obesity agents in PCOS for reproductive outcomes only in research settings to establish the efficacy and safety.

Table 1 : Categories of the PCOS guideline recommendations
EBREvidence-based recommendations: Evidence sufficient to inform a recommendation made by the guideline development group.

Table 3 :
RecommendationsThe recommendation and technical report numbers correspond.Consensus recommendations (CR) and practice points (PP) do not have 'GRADE' ratings, however the evidence summaries outline how they were informed by PCOS and general population evidence.# denoted priority for living guideline updates.

1 Screening, diagnostic and risk assessment and life stages
• be aware that standardised 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 presence of acne • recognise that women commonly treat clinical hyperandrogenism cosmetically, diminishing 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 • be aware 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 pattern hair loss, for improvement or treatment adjustment during therapy.1.

4 Ultrasound and polycystic ovarian morphology
PPThere are no definitive criteria to define polycystic ovary morphology (PCOM) on ultrasound in adolescents, hence it is not recommended in adolescents.
1.4.1EBRFollicle number per ovary (FNPO) should be considered the most effective ultrasound marker to detect polycystic ovarian morphology (PCOM) in adults.1.4.2EBR Follicle number per ovary (FNPO), follicle number per cross-section (FNPS) and ovarian volume (OV) should be considered accurate ultrasound markers for PCOM in adults.1.4.3CR PCOM criteria should be based on follicle excess (FNPO, FNPS) and/or ovarian enlargement (OV).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 throughout the entire ovary.1.4.10PP Thresholds for PCOM should be revised regularly with advancing ultrasound technology, and age-specific cut-off values for PCOM should be defined.1.4.11PP There is a need for training in careful and meticulous follicle counting per ovary and clear standardised 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, dominant 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 follicle is noted • uterine features and/or pathology including endometrial thickness and pattern.1.

5 Anti-mullerian hormone in the diagnosis of PCOS
1.5.1 EBR Serum anti-mullerian hormone (AMH) could be used for defining PCOM in adults.1.5.2EBRSerumAMH 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 necessary for PCOS diagnosis.•bodymassindex (BMI): Serum AMH is lower in those with higher BMI in the general population • hormonal contraception and ovarian surgery: Serum AMH may be suppressed by current 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.1.6Ethnicvariation1.6.1 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.1.6.2EBR Healthcare professionals should be aware that PCOS prevalence is similar across world regions and ethnicities, but may be higher in South East Asian and Eastern

Impaired glucose tolerance and type 2 diabetes risk
1.9.4 CR Healthcare professionals, women with PCOS and other stakeholders should prioritise preventative strategies to reduce type 2 diabetes risk.

screening and management of psychological features and models of care General principles PP Psychological
features are common and important component of PCOS that all health professionals should be aware of.
1.10.4PPGoals of treatment should target obstructive sleep apnea related symptom burden.
EBR Healthcare professionals should be aware of the high prevalence of moderate to severe depressive symptoms and depression in adults and adolescents with PCOS and should screen for depression in all adults and adolescents with PCOS, using regionally validated screening tools.2.2.2EBR 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 adults with PCOS, using regionally validated screening tools.
PPCulturally appropriate resources and education on PCOS across the life span for families of those with the condition, should be considered.EBR Healthcare professionals should employ shared decision making and support patient agency or ability to take independent actions to manage their health and care.
If an eating disorder or disordered eating is detected, appropriate management and support should be offered.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.
-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 (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.
PPAn OGTT should be offered to all women with PCOS when planning pregnancy or seeking fertility treatment, given the high risk of hyperglycaemia and the associated comorbidities in pregnancy.If not performed in the preconception phase, an OGTT should be offered at the first antenatal visit and repeated at 24-28 weeks gestation.