EBR

Evidence-based recommendations are made where evidence is sufficient to inform a recommendation made by the guideline development group.

CCR

Clinical consensus recommendations are made in the absence of adequate evidence on PCOS. These are informed by evidence in other populations and are made by the guideline development group, using rigorous and transparent processes.

CPP

Clinical practice points are made where evidence was not sought and are made where important clinical issues arose from discussion of evidence-based or clinical consensus recommendations.

High

⊕⊕⊕⊕

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

Moderate

⊕⊕⊕○

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

Low

⊕⊕○○

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

Very Low

⊕○○○

Very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Recommendation

GRADE and Quality

1. SCREENING, DIAGNOSTIC ASSESSMENT, RISK ASSESSMENT, AND LIFE-STAGE

 Irregular cycles and ovulatory dysfunction

CCR

●        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

•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 the guidelines

****

CCR

In an adolescent with irregular menstrual cycles, the value and optimal timing of assessment and diagnosis of PCOS should be discussed with the patient, taking into account diagnostic challenges at this life stage and psychosocial and cultural factors

****

CPP

For adolescents who have features of PCOS but do not meet diagnostic criteria, an “increased 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.

CPP

Ovulatory dysfunction can still occur with regular cycles and if anovulation needs to be confirmed serum progesterone levels can be measured.

_

 Biochemical hyperandrogenism

EBR

Calculated free testosterone, free androgen index, or calculated bioavailable testosterone should be used to assess biochemical hyperandrogenism in the diagnosis of PCOS.

****

⊕⊕○○

EBR

High quality assays such as liquid chromatography–mass spectrometry (LCMS) and extraction/chromatography immunoassays, should be used for the most accurate assessment of total or free testosterone in PCOS.

***

⊕⊕○○

EBR

Androstenedione and dehydroepiandrosterone sulfate (DHEAS) could be considered if total or free testosterone are not elevated; however, these provide limited additional information in the diagnosis of PCOS.

***

⊕⊕○○

CCR

Direct free testosterone assays, such as radiometric or enzyme-linked assays, preferably should not be used in assessment of biochemical hyperandrogenism in PCOS, as they demonstrate poor sensitivity, accuracy and precision.

CPP

Reliable assessment of biochemical hyperandrogenism is not possible in women on hormonal contraception, due to effects on sex hormone-binding globulin and altered gonadotrophin-dependent androgen production.

_

CPP

Where assessment of biochemical hyperandrogenism is important in women on hormonal contraception, drug withdrawal is recommended for three months or longer before measurement, and contraception management with a non-hormonal alternative is needed during this time.

_

CPP

Assessment of biochemical hyperandrogenism is most useful in establishing the diagnosis of PCOS and/or phenotype where clinical signs of hyperandrogenism (in particular hirsutism) are unclear or absent.

_

CPP

Interpretation of androgen levels needs to be guided by the reference ranges of the laboratory used, acknowledging that ranges for different methods and laboratories vary widely. Normal values are ideally based on levels from a well phenotyped healthy control population or by cluster analysis of a large general population considering age and pubertal specific stages.

_

CPP

Where androgen levels are markedly above laboratory reference ranges, other causes of biochemical hyperandrogenism need to be considered. History of symptom onset and progression is critical in assessing for neoplasia, however, some androgen-secreting neoplasms may only induce mild to moderate increases in biochemical hyperandrogenism.

_

 Clinical hyperandrogenism

CCR

A comprehensive history and physical examination should be completed for symptoms and signs of clinical hyperandrogenism, including acne, alopecia, and hirsutism and, in adolescents, severe acne and hirsutism.

****

CCR

Health professionals should be aware of the potential negative psychosocial impact of clinical hyperandrogenism. Reported unwanted excess hair growth and/or alopecia should be considered important, regardless of apparent clinical severity.

****

CCR

Standardized visual scales are preferred when assessing hirsutism, such as the modified Ferriman Gallwey score (mFG) with a level ≥ 4-6 indicating hirsutism, depending on ethnicity, acknowledging that self-treatment is common and can limit clinical assessment. (See recommendations on ethnic variation.)

****

CCR

The Ludwig visual score is preferred for assessing the degree and distribution of alopecia.

****

CPP

There are no universally accepted visual assessments for evaluating acne.

CPP

The prevalence of hirsutism is the same across ethnicities, yet the mFG cut-off scores for defining hirsutism and the severity of hirsutism varies by ethnicity.

_

CPP

As ethnic variation in vellus hair density is notable, over-estimation of hirsutism may occur if vellus hair is confused with terminal hair; only terminal hairs need to be considered in pathological hirsutism, with terminal hairs clinically growing > 5 mm in length if untreated, varying in shape and texture and generally being pigmented.

_

 Ultrasound and polycystic ovarian morphology (PCOM)

CCR

Ultrasound should not be used for the diagnosis of PCOS in those with a gynecological age of <8 years (<8 years after menarche), due to the high incidence of multi-follicular ovaries in this life stage.

****

CCR

The threshold for PCOM should be revised regularly with advancing ultrasound technology, and age-specific cut off values for PCOM should be defined.

****

CCR

The transvaginal ultrasound approach is preferred in the diagnosis of PCOS, if sexually active and if acceptable to the individual being assessed.

****

CCR

Using endovaginal ultrasound transducers with a frequency bandwidth that includes 8 MHz, the threshold for PCOM on either ovary, a follicle number per ovary of ≥20 and/or an ovarian volume ≥ 10 ml on either ovary, ensuring no corpora lutea, cysts or dominant follicles are present.

***

CPP

If using older technology, the threshold for PCOM could be an ovarian volume ≥ 10 ml on either ovary.

_

CPP

In patients with irregular menstrual cycles and hyperandrogenism, an ovarian ultrasound is not necessary for PCOS diagnosis; however, ultrasound will identify the complete PCOS phenotype.

_

CPP

In transabdominal ultrasound reporting is best focused on ovarian volume with a threshold of ≥ 10 ml, given the difficulty of reliably assessing follicle number with this approach.

_

CPP

●        Clear protocols are recommended for reporting follicle number per ovary and ovarian volume on ultrasound. Recommended minimum reporting standards include:

•Last menstrual period

•Transducer bandwidth frequency

•Approach/route assessed

•Total follicle number per ovary measuring 2-9 mm

•Three dimensions and volume of each ovary

•Reporting of endometrial thickness and appearance is preferred; 3-layer endometrial assessment may be useful to screen for endometrial pathology

•Other ovarian and uterine pathology, as well as ovarian cysts, corpus luteum, dominant follicles ≥ 10 mm

_

CPP

There is a need for training in careful and meticulous follicle counting per ovary, to improve reporting.

_

 Anti-müllerian hormone (AMH)

EBR

Serum AMH levels should not yet be used as an alternative for the detection of PCOM or as a single test for the diagnosis of PCOS.

***

⊕⊕○○

CPP

There is emerging evidence that with improved standardization of assays and established cut off levels or thresholds based on large scale validation in populations of different ages and ethnicities, AMH assays will be more accurate in the detection of PCOM.

_

 Ethnic variation

CCR

●        Health professionals should consider ethnic variation in the presentation and manifestations of PCOS, including:

•A relatively mild phenotype in Caucasians

•Higher body mass index (BMI) in Caucasian women, especially in North America and Australia

•More severe hirsutism in Middle Eastern, Hispanic, and Mediterranean women

•Increased central adiposity, insulin resistance, diabetes, metabolic risks, and acanthosis nigricans in South East Asians and Indigenous Australians

•Lower BMI and milder hirsutism in East Asians

•Higher BMI and metabolic features in Africans

****

 Menopause life stage

CCR

Postmenopausal persistence of PCOS could be considered likely with continuing evidence of hyperandrogenism.

***

CCR

A diagnosis of PCOS postmenopause could be considered if there is a past diagnosis of PCOS, a long-term history of irregular menstrual cycles and hyperandrogenism and/or PCOM, during the reproductive years.

***

CPP

Postmenopausal women presenting with new-onset, severe or worsening hyperandrogenism including hirsutism, require investigation to rule out androgen-secreting tumors and ovarian hyperthecosis.

_

 Cardiovascular disease risk (CVD)

CCR

All those with PCOS should be offered regular monitoring for weight changes and excess weight, in consultation with and where acceptable to the individual woman. Monitoring could be at each visit or at a minimum 6-12 monthly, with frequency planned and agreed between the health professional and the individual.

****

CCR

●        Weight, height, and ideally waist circumference should be measured and BMI calculated with the following considered:

•BMI categories and waist circumference should follow World Health Organization guidelines, also noting ethnic and adolescent ranges.

•Consideration should be given for Asian and high-risk ethnic groups including recommended monitoring of waist circumference.

****

CCR

All women with PCOS should be assessed for cardiovascular risk factors and global CVD risk.

****

CCR

If screening reveals CVD risk factors including obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and lack of physical activity, women with PCOS should be considered at increased risk of CVD.

****

CCR

Overweight and obese women with PCOS, regardless of age, should have a fasting 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 hyperlipidemia and global CVD risk.

****

CCR

All women with PCOS should have blood pressure measured annually, or more frequently based on global CVD risk.

****

CPP

Health professionals need to be aware that CVD risk in women with PCOS remains unclear pending high quality studies, however prevalence of CVD risk factors is increased, warranting consideration of screening.

_

CPP

Consideration needs to be given to the significant differences in CVD risk across ethnicities (See Ethnic variation) when determining frequency of risk assessment.

_

 Gestational diabetes, impaired glucose tolerance and type 2 diabetes

CCR

Health professionals and women with PCOS should be aware that, regardless of age, the prevalence of gestational diabetes, impaired glucose tolerance and type 2 diabetes (5-fold in Asia, 4-fold in the Americas, and 3-fold in Europe) are significantly increased in PCOS, with risk independent of, yet exacerbated by, obesity.

****

CCR

Glycemic status should be assessed at baseline in all women with PCOS. Thereafter, assessment should be every one to three years, influenced by the presence of other diabetes risk factors.

****

CCR

An oral glucose tolerance test (OGTT), fasting plasma glucose or HbA1c should be performed to assess glycemic status. In high-risk women with PCOS (including a BMI > 25 kg/m² or in Asians > 23 kg/m², history of impaired fasting glucose, impaired glucose tolerance or gestational diabetes, family history of diabetes mellitus type 2, hypertension or high-risk ethnicity), an OGTT is recommended.

****

CCR

A 75-g OGTT should be offered in all women with PCOS preconception when planning pregnancy or seeking fertility treatment, given the high risk of hyperglycemia and the associated comorbidities in pregnancy. If not performed preconception, an OGTT should be offered at < 20 weeks gestation, and all women with PCOS should be offered the test at 24-28 weeks gestation.

****

 Obstructive sleep apnea (OSA)

CCR

Screening should only be considered for OSA in PCOS to identify and alleviate related symptoms, such as snoring, waking unrefreshed from sleep, daytime sleepiness, and the potential for fatigue to contribute to mood disorders. Screening should not be considered with the intention of improving cardiometabolic risk, with inadequate evidence for metabolic benefits of OSA treatment in PCOS and in general populations.

****

CCR

A simple screening questionnaire, preferably the Berlin tool, could be applied and if positive, referral to a specialist considered.

***

CPP

A positive screen raises the likelihood of OSA, however it does not quantify symptom burden and alone does not justify treatment. If women with PCOS have OSA symptoms and a positive screen, consideration can be given to referral to a specialist center for further evaluation.

_

 Endometrial cancer

CCR

Health professionals and women with PCOS should be aware of a 2- to 6-fold increased risk of endometrial cancer, which often presents before menopause; however absolute risk of endometrial cancer remains relatively low.

***

CPP

Health professionals require a low threshold for investigation of endometrial cancer in women with PCOS or a history of PCOS, with investigation by transvaginal ultrasound and/or endometrial biopsy recommended with persistent thickened endometrium and/or risk factors including prolonged amenorrhea, abnormal vaginal bleeding or excess weight. However, routine ultrasound screening of endometrial thickness in PCOS is not recommended.

_

CPP

Optimal prevention for endometrial hyperplasia and endometrial cancer is not known. A pragmatic approach could include COCP or progestin therapy in those with cycles longer than 90 days.

_

2. PREVALENCE, SCREENING, DIAGNOSTIC ASSESSMENT AND TREATMENT IN EMOTIONAL WELLBEING

 Quality of life

CCR

Health professionals and women should be aware of the adverse impact of PCOS on quality of life.

****

CCR

Health professionals should capture and consider perceptions of symptoms, impact on quality of life and personal priorities for care to improve patient outcomes.

****

CPP

The PCOS quality of life tool (PCOSQ), or the modified PCOSQ, may be useful clinically to highlight PCOS features causing greatest distress, and to evaluate treatment outcomes on women’s subjective PCOS health concerns.

_

 Depressive and anxiety symptoms, screening and treatment

CCR

Health professionals should be aware that in PCOS, there is a high prevalence of moderate to severe anxiety and depressive symptoms in adults; and a likely increased prevalence in adolescents.

****

CCR

Anxiety and depressive symptoms should be routinely screened in all adolescents and women with PCOS at diagnosis. If the screen for these symptoms and/or other aspects of emotional wellbeing is positive, further assessment and/or referral for assessment and treatment should be completed by suitably qualified health professionals, informed by regional guidelines.

****

CCR

If treatment is warranted, psychological therapy and/or pharmacological treatment should be offered in PCOS, informed by regional clinical practice guidelines.

****

CPP

The optimal interval for anxiety and depressive symptom screening is not known. A pragmatic approach could include repeat screening using clinical judgment, considering risk factors, comorbidities and life events.

_

CPP

Assessment of anxiety and or depressive symptoms involves assessment of risk factors, symptoms and severity. Symptoms can be screened according to regional guidelines, or by using simple stepwise approaches (see full guideline for details).

_

CPP

●        Where pharmacological treatment for anxiety and depression is offered in PCOS, the following need consideration:

•Caution is needed to avoid inappropriate treatment with antidepressants or anxiolytics. Where mental health disorders are clearly documented and persistent, or if suicidal symptoms are present, treatment of depression or anxiety need to be informed by clinical regional practice guidelines.

•Use of agents that exacerbate PCOS symptoms, including weight gain, need careful consideration.

_

CPP

Factors including obesity, infertility, and hirsutism need consideration along with use of hormonal medications in PCOS, as they may independently exacerbate depressive and anxiety symptoms and other aspects of emotional wellbeing.

_

 Psychosexual function

CCR

All health professionals should be aware of the increased prevalence of psychosexual dysfunction and should consider exploring how features of PCOS, including hirsutism and body image, impact on sex life and relationships in PCOS.

****

CCR

If psychosexual dysfunction is suspected, tools such as the Female Sexual Function Index can be considered.

****

 Body Image

CCR

Health professionals and women should be aware that features of PCOS can impact on body image.

***

CPP

Negative body image, can be screened according to regional guidelines or by using a stepped approach (see full guideline for details.

_

 Eating disorders and disordered eating

CCR

All health professionals and women should be aware of the increased prevalence of eating disorders and disordered eating associated with PCOS.

**

CCR

If eating disorders and disordered eating are suspected, further assessment, referral and treatment, including psychological therapy, could be offered by appropriately trained health professionals, informed by regional guidelines or by using a stepped approach (see full guideline for details).

**

 Information resources, models of care, cultural and linguistic considerations

CCR

Information and education resources for women with PCOS should be culturally appropriate, tailored and high-quality, should use a respectful and empathetic approach, and promote self-care and highlight peer support groups.

****

CCR

Information and education resources for healthcare professionals should promote the recommended diagnostic criteria, appropriate screening for comorbidities, and effective lifestyle and pharmacological management.

****

CCR

PCOS information should be comprehensive, evidence-based, and inclusive of the biopsychosocial dimensions of PCOS across the life-span.

****

CCR

Women’s needs, communication preferences, beliefs, and culture should be considered and addressed through provision of culturally and linguistically appropriate co-designed resources and care.

****

CPP

Interdisciplinary care needs to be considered for those with PCOS where appropriate and available. Primary care is generally well placed to diagnose, screen and coordinate interdisciplinary care.

_

CPP

Care needs to be person centered, address women’s priorities and be provided in partnership with those with PCOS and where appropriate, their families.

_

CPP

Guideline dissemination and translation including multimodal education tools and resources is important, with consultation and engagement with stakeholders internationally.

_

3. LIFESTYLE

 Effectiveness of lifestyle interventions

CCR

Healthy lifestyle behaviors encompassing healthy eating and regular physical activity should be recommended in all those with PCOS to achieve and/or maintain healthy weight and to optimize hormonal outcomes, general health, and quality of life across the life course.

****

EBR

Lifestyle intervention (preferably multicomponent including diet, exercise and behavioral strategies) should be recommended in all those with PCOS and excess weight, for reductions in weight, central obesity and insulin resistance.

***

⊕⊕○○

CPP

Achievable goals such as 5% to 10% weight loss in those with excess weight yields significant clinical improvements and is considered successful weight reduction within six months. Ongoing assessment and monitoring is important during weight loss and maintenance in all women with PCOS.

_

CPP

SMART (Specific Measurable, Achievable, Realistic and Timely) goal setting and self-monitoring can enable achievement of realistic lifestyle goals.

_

CPP

Psychological factors such as anxiety and depressive symptoms, body image concerns and disordered eating, need consideration and management to optimize engagement and adherence to lifestyle interventions.

_

CPP

Health professional interactions around healthy lifestyle, including diet and exercise, need to be respectful, patient-centred and to value women’s individualised healthy lifestyle preferences and cultural, socioeconomic and ethnic differences. Health professionals need to also consider personal sensitivities, marginalisation and potential weight-related stigma.

_

CPP

Adolescent and ethnic-specific BMI and waist circumference categories need to be considered when optimising lifestyle and weight.

_

CPP

Healthy lifestyle may contribute to health and quality of life benefits in the absence of weight loss.

_

CPP

Healthy lifestyle and optimal weight management appears equally effective in PCOS as in the general population and is the joint responsibility of all health professionals, partnering with women with PCOS. Where complex issues arise, referral to suitably trained allied health professionals needs to be considered.

_

CPP

Ethnic groups with PCOS who are at high cardiometabolic risk require greater consideration in terms of healthy lifestyle and lifestyle intervention (see Ethnic Variation).

_

 Behavioral strategies

CCR

Lifestyle interventions could include behavioral strategies such as goal-setting, self-monitoring, stimulus control, problem solving, assertiveness training, slower eating, reinforcing changes and relapse prevention, to optimize weight management, healthy lifestyle and emotional wellbeing in women with PCOS.

****

CPP

Comprehensive health behavioral or cognitive behavioral interventions could be considered to increase support, engagement, retention, adherence and maintenance of healthy lifestyle and improve health outcomes in women with PCOS.

_

 Dietary intervention

CCR

A variety of balanced dietary approaches could be recommended to reduce dietary energy intake and induce weight loss in women with PCOS and overweight and obesity, as per general population recommendations.

****

CCR

General healthy eating principles should be followed for all women with PCOS across the life course, as per general population recommendations.

****

CPP

To achieve weight loss in those with excess weight, an energy deficit of 30% or 500-750 kcal/day (1,200 to 1,500 kcal/day) could be prescribed for women, also considering individual energy requirements, body weight and physical activity levels.

_

CPP

In women with PCOS, there is no or limited evidence that any specific energy equivalent diet type is better than another, or that there is any differential response to weight management intervention, compared to women without PCOS.

_

CPP

Tailoring of dietary changes to food preferences, allowing for a flexible and individual approach to reducing energy intake and avoiding unduly restrictive and nutritionally unbalanced diets, are important, as per general population recommendations.

_

 Exercise intervention

CCR

●        Health professionals should encourage and advise the following for prevention of weight gain and maintenance of health:

●         

•In adults from 18 – 64 years, a minimum of 150 min/week of moderate intensity physical activity or 75 min/week of vigorous intensities or an equivalent combination of both, including muscle strengthening activities on 2 non-consecutive days/week

•In adolescents, at least 60 minutes of moderate to vigorous intensity physical activity/day, including those that strengthen muscle and bone at least 3 times weekly

•Activity be performed in at least 10-minute bouts or around 1000 steps, aiming to achieve at least 30 minutes daily on most days.

***

CCR

●        Health professionals should encourage and advise the following for modest weight-loss, prevention of weight-regain and greater health benefits:

•A minimum of 250 min/week of moderate intensity activities or 150 min/week of vigorous intensity or an equivalent combination of both, and muscle strengthening activities involving major muscle groups on 2 non-consecutive days/week

•Minimized sedentary, screen, or sitting time.

***

CPP

Physical activity includes leisure time physical activity, transportation such as walking or cycling, occupational work, household chores, games, sports or planned exercise, in the context of daily, family and community activities. Daily, 10000 steps is ideal, including activities of daily living and 30 minutes of structured physical activity or around 3000 steps. Structuring of recommended activities need to consider women’s and family routines as well as cultural preferences

_

CPP

Realistic physical activity SMART (Specific, Measureable, Achievable, Relevant, Time limited) goals could include 10 minute bouts, progressively increasing physical activity 5% weekly, up to and above recommendations.

_

CPP

Self-monitoring including with fitness tracking devices and technologies for step count and exercise intensity, could be used as an adjunct to support and promote active lifestyles and minimize sedentary behaviors.

_

 Obesity and weight assessment

CCR

Health professionals and women should be aware that women with PCOS have a higher prevalence of weight gain and obesity, presenting significant concerns for women, impacting on health and emotional wellbeing, with a clear need for prevention.

***

CCR

All those with PCOS should be offered regular monitoring for weight changes and excess weight (see Cardiovascular Disease Risk).

****

CPP

When assessing weight, related stigma, negative body image and/or low self-esteem need to be considered and assessment needs to be respectful and considerate. Beforehand, explanations on the purpose and how the information will be used and the opportunity for questions and preferences needs to be provided, permission sought and scales and tape measures adequate. Implications of results need to be explained and where this impacts on emotional wellbeing, support provided.

_

CPP

Prevention of weight gain, monitoring of weight and encouraging evidence-based and socio-culturally appropriate healthy lifestyle is important in PCOS, particularly from adolescence.

_

4. PHARMACOLOGICAL TREATMENT FOR NON-FERTILITY INDICATIONS

 Pharmacological treatment principles in PCOS

CPP

Consideration of the individual’s personal characteristics, preferences and values is important in recommending pharmacological treatment.

_

CPP

When prescribing pharmacological therapy in PCOS, benefits, adverse effects and contraindications in PCOS and general populations need to be considered and discussed before commencement.

_

CPP

COCPs, metformin and other pharmacological treatments are generally off label^# in PCOS. However off label use is predominantly evidence-based and is allowed in many countries. Where it is allowed, health professionals need to inform women and discuss the evidence, possible concerns and side effects of treatment.

_

CPP

Holistic approaches are required and pharmacological therapy in PCOS needs to be considered alongside education, lifestyle and other options including cosmetic therapy and counselling.

_

 Combined oral contraceptive pills (COCPs)

EBR

The COCP alone should be recommended in adult women with PCOS for management of hyperandrogenism and/or irregular menstrual cycles.

****

⊕⊕○○

EBR

The COCP alone should be considered in adolescents with a clear diagnosis of PCOS for management of clinical hyperandrogenism and/or irregular menstrual cycles.

***

⊕⊕○○

EBR

The COCP could be considered in adolescents who are deemed “at risk” but not yet diagnosed with PCOS, for management of clinical hyperandrogenism and irregular menstrual cycles.

***

⊕⊕○○

EBR

Specific types or dose of progestins, estrogens or combinations of COCP cannot currently be recommended in adults and adolescents with PCOS and practice should be informed by general population guidelines.

***

⊕⊕○○

CCR

The 35 microgram ethinyloestradiol plus cyproterone acetate preparations should not be considered first line in PCOS as per general population guidelines, due to adverse effects including venous thromboembolic risks.

*

CPP

●        When prescribing COCPs in adults and adolescents with PCOS:

•Various COCP preparations have similar efficacy in treating hirsutism

•The lowest effective estrogen doses (such as 20-30 micrograms of ethinyloestradiol or equivalent), and natural estrogen preparations are preferred, balancing efficacy, metabolic risk profile, side effects, cost and availability

•The generally limited evidence on effects of COCPs in PCOS needs to be appreciated with practice informed by general population guidelines (WHO Guidelines)

•The relative and absolute contraindications and side effects of COCPs need to be considered and be the subject of individualized discussion

•PCOS specific risk factors such as high BMI, hyperlipidemia and hypertension need to be considered.

_

 Combined oral contraceptive pills in combination with metformin and/or anti-androgen pharmacological agents

EBR

In combination with the COCP, metformin should be considered in women with PCOS for management of metabolic features where COCP and lifestyle changes do not achieve desired goals.

****

⊕⊕○○

EBR

In combination with the COCP, metformin could be considered in adolescents with PCOS and BMI ≥ 25 kg/m² where COCP and lifestyle changes do not achieve desired goals.

****

⊕⊕○○

CPP

In combination with the COCP, metformin may be most beneficial in high metabolic risk groups including those with diabetes risk factors, impaired glucose tolerance, or high-risk ethnic groups.

_

EBR

In combination with the COCP, antiandrogens should only be considered in PCOS to treat hirsutism, after six months or more of COCP and cosmetic therapy have failed to adequately improve symptoms.

**

⊕⊕○○

CCR

In combination with the COCP, antiandrogens could be considered for the treatment of androgen-related alopecia in PCOS.

**

CPP

In PCOS, antiandrogens must be used with effective contraception, to avoid male foetal undervirilisation. Variable availability and regulatory status of these agents is notable and for some agents, potential liver toxicity requires caution.

_

 Metformin

EBR

Metformin in addition to lifestyle, could be recommended in adult women with PCOS, for the treatment of weight, hormonal, and metabolic outcomes.

***

⊕⊕○○

EBR

Metformin in addition to lifestyle, should be considered in adult women with PCOS with BMI ≥ 25 kg/m² for management of weight and metabolic outcomes.

***

⊕⊕○○

EBR

Metformin in additional to lifestyle, could be considered in adolescents with a clear diagnosis of PCOS or with symptoms of PCOS before the diagnosis is made.

***

⊕⊕○○

CPP

Metformin may offer greater benefit in high metabolic risk groups including those with diabetes risk factors, impaired glucose tolerance or high-risk ethnic groups (see Ethnic variation)

_

CPP

●        Where metformin is prescribed the following need to be considered:

•Adverse effects, including gastrointestinal side-effects that are generally dose dependent and self-limiting, need to be the subject of individualized discussion

•Starting at a low dose, with 500 mg increments 1-2 weekly and extended release preparations may minimize side effects

•Metformin use appears safe long-term, based on use in other populations, however ongoing requirement needs to be considered and use may be associated with low vitamin B12 levels

•Use is generally off label and health professionals need to inform women and discuss the evidence, possible concerns and side effects.

_

Anti-obesity pharmacological agents

CCR

Anti-obesity medications in addition to lifestyle, could be considered for the management of obesity in adults with PCOS after lifestyle intervention, as per general population recommendations.

_

CPP

For anti-obesity medications, cost, contraindications, side effects, variable availability and regulatory status need to be considered and pregnancy needs to be avoided whilst taking these medications.

_

 Anti-androgen pharmacological agents

EBR

Where COCPs are contraindicated or poorly tolerated, in the presence of other effective forms of contraception, anti-androgens could be considered to treat hirsutism and androgen-related alopecia.

***

⊕○○○

CPP

Specific types or doses of anti-androgens cannot currently be recommended with inadequate evidence in PCOS.

_

 Inositol

EBR

Inositol (in any form) should currently be considered an experimental therapy in PCOS, with emerging evidence on efficacy highlighting the need for further research.

*

⊕○○○

CPP

Women taking inositol and other complementary therapies are encouraged to advise their health professional.

_

5. ASSESSMENT AND TREATMENT OF INFERTILITY

 Assessment of factors that may affect fertility, treatment response, or pregnancy outcomes

CPP

Factors such as blood glucose, weight, blood pressure, smoking, alcohol, diet, exercise, sleep and mental, emotional and sexual health need to be optimized in women with PCOS, to improve reproductive and obstetric outcomes, aligned with recommendations in the general population. Refer to Lifestyle, Emotional Wellbeing and Diabetes risk sections.

_

CPP

Monitoring during pregnancy is important in women with PCOS, given increased risk of adverse maternal and offspring outcomes.

_

CCR

In women with PCOS and infertility due to anovulation alone with normal semen analysis, the risks, benefits, costs and timing of tubal patency testing should be discussed on an individual basis.

***

CCR

Tubal patency testing should be considered prior to ovulation induction in women with PCOS where there is suspected tubal infertility.

***

 Ovulation induction principles

CPP

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, health professionals need to inform women and discuss the evidence, possible concerns and side effects.

_

CPP

Pregnancy needs to be excluded prior to ovulation induction.

_

CPP

Unsuccessful, prolonged use of ovulation induction agents need to be avoided, due to poor success rates.

_

 Letrozole

EBR

Letrozole should be considered first line pharmacological treatment for ovulation induction in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, pregnancy and live birth rates.

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CPP

Where letrozole is not available or use is not permitted or cost is prohibitive, health professionals can use other ovulation induction agents.

_

CPP

Health professionals and women need to be aware that the risk of multiple pregnancy appears to be less with letrozole, compared to clomiphene citrate.

_

 Clomiphene citrate and metformin

EBR

Clomiphene citrate could be used alone in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation and pregnancy rates.

***

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EBR

Metformin could be used alone in women with PCOS, with anovulatory infertility and no other infertility factors, to improve ovulation, pregnancy and live birth rates, although women should be informed that there are more effective ovulation induction agents.

***

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EBR

Clomiphene citrate could be used in preference, when considering clomiphene citrate or metformin for ovulation induction in women with PCOS who are obese (BMI is ≥ 30 kg/m²) with anovulatory infertility and no other infertility factors.

***

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EBR

If metformin is being used for ovulation induction in women with PCOS who are obese (BMI ≥ 30 kg/m²) with anovulatory infertility and no other infertility factors, clomiphene citrate could be added to improve ovulation, pregnancy and live birth rates.

***

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EBR

Clomiphene citrate could be combined with metformin, rather than persisting with clomiphene citrate alone, in women with PCOS who are clomiphene citrate-resistant, with anovulatory infertility and no other infertility factors, to improve ovulation and pregnancy rates.

***

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CPP

The risk of multiple pregnancies is increased with clomiphene citrate use and therefore monitoring needs to be considered.

_

 Gonadotrophins

EBR

Gonadotrophins could be used as second line pharmacological agents in women with PCOS who have failed first line oral ovulation induction therapy and are anovulatory and infertile, with no other infertility factors.

***

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EBR

Gonadotrophins could be considered as first line treatment, in the presence of ultrasound monitoring, following counselling on cost and potential risk of multiple pregnancy, in women with PCOS with anovulatory infertility and no other infertility factors.

***

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EBR

Gonadotrophins, where available and affordable, should be used in preference to clomiphene citrate combined with metformin therapy for ovulation induction, in women with PCOS with anovulatory infertility, clomiphene citrate-resistance and no other infertility factors, to improve ovulation, pregnancy and live birth rates.

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EBR

Gonadotrophins with the addition of metformin could be used rather than gonadotrophin alone, in women with PCOS with anovulatory infertility, clomiphene citrate-resistance and no other infertility factors, to improve ovulation, pregnancy and live birth rates.

***

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EBR

Either gonadotrophins or laparoscopic ovarian surgery could be used in women with PCOS with anovulatory infertility, clomiphene citrate-resistance and no other infertility factors, following counselling on benefits and risks of each therapy.

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CPP

●        Where gonadotrophins are prescribed, considerations include:

•Cost and availability

•Expertise required for use in ovulation induction

•Degree of intensive ultrasound monitoring required

•Lack of difference in clinical efficacy of available gonadotrophin preparations

•Low dose gonadotrophin protocols optimize monofollicular development

•Risk and implications of potential multiple pregnancy

_

CPP

Gonadotrophin induced ovulation is only triggered when there are fewer than three mature follicles and needs to be cancelled if there are more than two mature follicles with the patient advised to avoid unprotected intercourse.

_

 Anti-obesity pharmacological agents

CCR

Pharmacological anti-obesity agents should be considered an experimental therapy in women with PCOS for the purpose of improving fertility, with risk to benefit ratios currently too uncertain to advocate this as fertility therapy.

*

 Laparoscopic surgery

EBR

Laparoscopic ovarian surgery could be second line therapy for women with PCOS, who are clomiphene citrate resistant, with anovulatory infertility and no other infertility factors.

***

⊕⊕○○

CCR

Laparoscopic ovarian surgery could potentially be offered as first line treatment if laparoscopy is indicated for another reason in women with PCOS with anovulatory infertility and no other infertility factors.

***

CPP

Risks need to be explained to all women with PCOS considering laparoscopic ovarian surgery.

_

CPP

●        Where laparoscopic ovarian surgery is to be recommended, the following need to be considered:

•Comparative cost

•Expertise required for use in ovulation induction

•Intra-operative and post-operative risks are higher in women who are overweight and obese

•There may be a small associated risk of lower ovarian reserve or loss of ovarian function

•Periadnexal adhesion formation may be an associated risk.

_

 Bariatric surgery

CCR

Bariatric surgery should be considered an experimental therapy in women with PCOS, for the purpose of having a healthy baby, with risk to benefit ratios currently too uncertain to advocate this as fertility therapy.

*

CPP

●        If bariatric surgery is to be prescribed, the following need to be considered:

• Comparative cost

• The need for a structured weight management program involving diet, physical activity and interventions to improve psychological, musculoskeletal and cardiovascular health to continue post-operatively

• Perinatal risks such as small for gestational age, premature delivery, possibly increased infant mortality

•Potential benefits such as reduced incidence of large for gestational age fetus and gestational diabetes

•Recommendations for pregnancy avoidance during periods of rapid weight loss and for at least 12 months after bariatric surgery with appropriate contraception.

●        If pregnancy occurs, the following need to be considered:

•Awareness and preventative management of pre-and post-operative nutritional deficiencies is important, ideally in a specialist interdisciplinary care setting

•Monitoring of fetal growth during pregnancy.

_

 In vitro fertilization (IVF)

CCR

In the absence of an absolute indication for IVF ± intracytoplasmic sperm injection (ICSI), women with PCOS and anovulatory infertility could be offered IVF as third line therapy where first or second line ovulation induction therapies have failed.

***

CPP

In women with anovulatory PCOS, the use of IVF is effective and when elective single embryo transfer is used, multiple pregnancies can be minimized.

_

CPP

●        Women with PCOS undergoing IVF ± ICSI therapy need to be counselled prior to starting treatment including on:

•Availability, cost and convenience

• Increased risk of ovarian hyperstimulation syndrome

•Options to reduce the risk of ovarian hyperstimulation.

_

CCR

Urinary or recombinant follicle stimulation hormone can be used in women with PCOS undergoing controlled ovarian hyperstimulation for IVF ± ICSI, with insufficient evidence to recommend specific follicle stimulating hormone (FSH) preparations.

_

CCR

Exogenous recombinant luteinizing hormone treatment should not be routinely used in combination with follicle stimulating hormone therapy in women with PCOS undergoing controlled ovarian hyperstimulation for IVF ± ICSI.

_

EBR

A gonadotrophin releasing hormone antagonist protocol is preferred in women with PCOS undergoing an IVF ± ICSI cycle, over a gonadotrophin releasing hormone agonist long protocol, to reduce the duration of stimulation, total gonadotrophin dose and incidence of ovarian hyperstimulation syndrome (OHSS).

***

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CPP

Human chorionic gonadotrophins is best used at the lowest doses to trigger final oocyte maturation in women with PCOS undergoing an IVF ± ICSI cycle to reduce the incidence of OHSS.

_

CPP

Triggering final oocyte maturation with a gonadotropin-releasing hormone (GnRH) agonist and freezing all suitable embryos could be considered in women with PCOS having an IVF/ICSI cycle with a GnRH antagonist protocol and at an increased risk of developing OHSS or where fresh embryo transfer is not planned.

_

CPP

In IVF ± ICSI cycles in women with PCOS, consideration needs to be given to an elective freeze of all embryos.

_

EBR

Adjunct metformin therapy could be used before and/or during follicle stimulating hormone ovarian stimulation in women with PCOS undergoing a IVF ± ICSI therapy with a GnRH agonist protocol, to improve the clinical pregnancy rate and reduce the risk of OHSS.

***

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CCR

●        In a GnRH agonist protocol with adjunct metformin therapy, in women with PCOS undergoing IVF ± ICSI treatment, the following could be considered:

•Metformin commencement at the start of GnRH agonist treatment

•Metformin use at a dose of between 1000 mg to 2550 mg daily

•Metformin cessation at the time of the pregnancy test or menses (unless the metformin therapy is otherwise indicated)

•Metformin side-effects (see metformin section in this table)

_

CPP

In IVF ± ICSI cycles, women with PCOS could be counselled on potential benefits of adjunct metformin in a GnRH antagonist protocol to reduce risk of ovarian hyperstimulation syndrome (see above for metformin therapy considerations).

_

CPP

The term in vitro maturation (IVM) treatment cycle is applied to “the maturation in vitro of immature cumulus oocyte complexes collected from antral follicles” (encompassing both stimulated and unstimulated cycles, but without the use of a human gonadotrophin trigger).

_

CCR