Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome†.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Outcomes of assisted reproductive technology procedures performed on weekdays versus weekends: a retrospective cohort study.

PURPOSE: To evaluate if assisted reproductive technology (ART) outcomes are different based on whether procedures - oocyte retrieval, insemination, embryo biopsy, or embryo transfer - are performed on a weekday versus weekend/holiday. METHODS: Retrospective cohort study of all patients ≥ 18 years old who underwent oocyte retrieval for in vitro fertilization or oocyte banking (n = 3,197 cycles), fresh or natural-cycle frozen embryo transfers (n = 1,739 transfers), or had embryos biopsied for pre-implantation genetic testing (n = 4,568 embryos) in a large academic practice from 2015-2020. The primary outcomes were as follows: oocyte maturity for oocyte retrievals; fertilization rate for insemination; rate of no result on pre-implantation genetic testing for embryo biopsy; and live birth rate for embryo transfers. RESULTS: The average number of procedures performed per embryologist per day was higher on weekends/holidays than weekdays. For oocyte retrievals performed on weekdays vs. weekends/holidays, there was no difference in oocyte maturity rate (88% vs 88%). There was no difference in the fertilization rate (82% vs 80%) in cycles that had intracytoplasmic sperm injection performed on weekdays vs. weekends/holidays. No difference was found in the no result rate for embryos biopsied on weekdays vs. weekends/holidays (2.5% vs 1.8%). Finally, there was no difference by weekday vs. weekend/holiday in the live birth rate per transfer among all transfers (39.6% vs 36.1%), or when stratified by fresh (35.1% vs 34.9%) or frozen embryo transfer (49.7% vs. 39.6%). CONCLUSION: We found no differences in ART outcomes among women who had their oocyte retrievals, inseminations, embryo biopsies, or embryo transfers performed on weekdays versus weekends/holidays.

Postpartum weight retention in women with polycystic ovary syndrome.

BACKGROUND: Compared with women without polycystic ovary syndrome, women with polycystic ovary syndrome have a higher prevalence of cardiometabolic risk factors. Postpartum weight retention has been shown to contribute to these risks in the general population, but little is known about postpartum weight retention among women with polycystic ovary syndrome. OBJECTIVE: This study aimed to compare postpartum weight retention and peripartum weight trends between women with polycystic ovary syndrome and controls. STUDY DESIGN: Data on live, full-term singleton deliveries from January 1, 2014, to January 1, 2019, in women with and without polycystic ovary syndrome were abstracted from the electronic medical record. Weights during the pregestational period, pregnancy, and up to 12 months postpartum were collected. The primary outcome was likelihood of high postpartum weight retention of ≥5 kg above pregestational weight at 12 months after delivery. Secondary outcomes included the prevalence of high weight retention at other postpartum time points (6 weeks, 3 months, 6 months), absolute postpartum weight retention, gestational weight gain, and excess weight gain above the Institute of Medicine guidelines for weight gain in pregnancy. RESULTS: A total of 6333 women had the requisite weight information (pregestational, peak pregnancy, and at least 1 postpartum weight), including 429 (6.8%) with polycystic ovary syndrome. After adjusting for age, pregestational body mass index, race, gestational diabetes mellitus, and parity, women with polycystic ovary syndrome were less likely to be high weight retainers at 6 weeks after delivery (adjusted odds ratio, 0.71; P=.02). There was no difference in postpartum weight retention between groups at 3, 6, and 12 months after delivery. Overall, the prevalence of high weight retainers at 12 months after delivery was high in both groups (22.7% in polycystic ovary syndrome vs 29.2% in controls; P=.13), and there was no difference in absolute weight retention (1.69 kg in polycystic ovary syndrome vs 2.05 kg in controls; P=.25). Although women with polycystic ovary syndrome had a higher pregestational body mass index, they had lower gestational weight gain (median, 12.7 kg) than controls (median, 13.5 kg) (P=.01). These findings were driven by the group with obesity. The percentage of women who surpassed the Institute of Medicine guidelines for gestational weight gain based on the body mass index category was similar between groups (43.4% in polycystic ovary syndrome vs 47.3% in controls; P=.12). Overall, 18.5% of women with polycystic ovary syndrome and 23.4% of controls had a higher body mass index category at 12 months after delivery than before pregnancy. CONCLUSION: Women with polycystic ovary syndrome had lower gestational weight gain and lower likelihood of high weight retention at 6 weeks after delivery but similar weight retention at 12 months after delivery compared with controls. Overall, the large proportion of women with high postpartum weight retention highlights the importance of the peripartum time period for weight management, particularly in this high-risk group predisposed to obesity and cardiometabolic disease.

Postpartum complications increased in women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome are at a higher risk of cardiometabolic and psychiatric comorbidities and preconception and antepartum complications, but the impact of polycystic ovary syndrome during the postpartum period is unknown. OBJECTIVE: This study aimed to investigate the risk of postpartum cardiovascular disease complications and perinatal and postpartum depression. STUDY DESIGN: This was a retrospective cohort study conducted using a United States insurance claims database. Women with and without polycystic ovary syndrome aged 18 to 50 years enrolled continuously in a single health plan during the preconception, antepartum, and postpartum periods between 2000 and 2016 were included. The primary outcome was postpartum cardiovascular disease and depression (perinatal and postpartum). Multivariable logistic regression was used to adjust for covariates including age, geographic location, preterm delivery, assisted reproductive technology use, multiple births, prepregnancy depression, prepregnancy diabetes, prepregnancy hypertension, gestational diabetes, gestational hypertension, obesity, history of hyperlipidemia, smoking, and race. RESULTS: We identified 42,391 unique women with polycystic ovary syndrome and 795,480 women without polycystic ovary syndrome. In multivariable models, women with polycystic ovary syndrome had significantly higher odds of cardiovascular disease complications, including postpartum preeclampsia (adjusted odds ratio, 1.30; 95% confidence interval, 1.17-1.45), eclampsia (adjusted odds ratio, 1.45; 95% confidence interval, 1.14-1.86) cardiomyopathy (adjusted odds ratio, 1.26; 95% confidence interval, 1.03-1.54), hypertensive heart disease (adjusted odds ratio, 1.32: 95% confidence interval, 1.07-1.64), thrombotic disease (adjusted odds ratio, 1.50; 95% confidence interval, 1.20-1.87), congestive heart failure (adjusted odds ratio, 1.35; 95% confidence interval, 1.13-1.61), and cerebrovascular accidents (adjusted odds ratio, 1.21; 95% confidence interval, 1.14-1.29), than those without polycystic ovary syndrome, as well as both perinatal (adjusted odds ratio, 1.27; 95% confidence interval, 1.22-1.33) and postpartum depression (adjusted odds ratio, 1.46; 95% confidence interval, 1.36-1.57). Nonobese women with polycystic ovary syndrome had higher odds of postpartum eclampsia (adjusted odds ratio 1.72; 95% confidence interval, 1.31-2.26), peripartum cardiomyopathy (adjusted odds ratio, 1.43; 95% confidence interval, 1.14-1.79), and cerebrovascular accidents (adjusted odds ratio, 1.28; 95% confidence interval, 1.19-1.38) than nonobese women without polycystic ovary syndrome. In the group of women without prepregnancy depression, the odds of perinatal depression (adjusted odds ratio, 1.32; 95% confidence interval, 1.26-1.39) and postpartum depression (adjusted odds ratio, 1.50; 95% confidence interval, 1.39-1.62) were higher in women with polycystic ovary syndrome than those without polycystic ovary syndrome. CONCLUSION: In a large United States cohort, our study found that women with polycystic ovary syndrome are at increased risk of both cardiovascular and psychiatric complications during the postpartum period. Polycystic ovary syndrome should be recognized as an at-risk condition; our findings underscore the need for routine screening and early interventions for these major comorbidities.

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Impact of a diagnosis of polycystic ovary syndrome on diet, physical activity and contraceptive use in young women: findings from the Australian Longitudinal Study of Women's Health.

STUDY QUESTION: Do diet, physical activity and contraceptive use change after receiving a diagnosis of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Using longitudinal data 12 months apart, young women newly diagnosed with PCOS were more likely to stop using contraception but did not change their physical activity or vegetable intake. WHAT IS KNOWN ALREADY: Diagnostic criteria for PCOS have widened to capture more women, despite limited evidence of the benefits and harms. Possible benefits of a PCOS diagnosis are that it may help women with family planning and motivate them to implement healthy lifestyle changes to reduce the reproductive, metabolic and cardiovascular risks associated with PCOS. However, there are no empirical studies investigating how women respond to a diagnosis of PCOS with respect to their health behaviour, and longitudinal population-based studies are lacking. STUDY DESIGN, SIZE, DURATION: This is a longitudinal analysis of two waves of data collected 12 months apart from the cohort born 1989-1995 in the Australian Longitudinal Survey on Women's Health, a population-based cohort study. Women in this cohort were first surveyed in 2012-2013, aged 18-23 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who responded to the 2014 survey (aged 19-24, n = 11 344) and 2015 survey (aged 20-25, n = 8961) were included. Using logistic regression, multinomial logistic regression and linear regression, change in vegetable intake, physical activity and contraceptive use were compared for women newly diagnosed with PCOS to women not reporting a diagnosis of PCOS. Changes in psychological distress and BMI were also examined. MAIN RESULTS AND THE ROLE OF CHANCE: Young women reporting a new diagnosis of PCOS were no more likely to increase their vegetable intake or physical activity than women not reporting a PCOS diagnosis. Women newly diagnosed with PCOS were 3.4 times more likely to stop using contraception during the 12-month study period than women without PCOS (14% versus 4%, 95% CI = 2.3 to 5.1, P < 0.001). This difference remained significant after controlling for demographics, chronic conditions associated with PCOS, endometriosis, BMI and psychological distress (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: All data was self-reported including PCOS diagnosis, assessment of diet quality was limited to vegetable intake only. The exact timing of diagnosis within the 12-month period and whether the women intended to conceive are unknown. The number of women reporting a new diagnosis of PCOS was also relatively small. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that a diagnosis of PCOS may not produce short-term benefits by way of improving health behaviour. The observed reduction in contraception use suggests some women may be at increased risk of unplanned pregnancies, highlighting the importance of counselling about contraceptive needs. Both potential benefits and harms must be considered when determining the appropriateness of a PCOS diagnosis. STUDY FUNDING/COMPETING INTEREST(S): The Australian Longitudinal Study on Women's Health is funded by the Australian Government Department of Health. BWM reports consultancy for ObsEva, Merck, Merck KGaA and Guerbet. No further competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Knowledge of PCOS in physicians-in-training: identifying gaps and educational opportunities.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. A recent study found that many obstetrics and gynecology (ObGyn) practicing physicians are unaware of the Rotterdam criteria recommended for diagnosis. Our objective was to identify gaps in trainee knowledge of PCOS diagnostic criteria and management. An online survey was sent out to US ObGyn physicians-in-training in 2018. The primary outcomes were identification of at least one component of each Rotterdam criteria (Rot-3): (1) oligomenorrhea/amenorrhea, (2) clinical or biochemical hyperandrogenism, and (3) ovarian volume or antral follicle count, and identification of all five components (Rot-5). Secondary outcomes were identification of comorbidities and management of PCOS. Multivariable logistic regression was used controlling for gender, seniority (PGY) status, program type, completion of an REI rotation, and number of PCOS patients seen. 85.4% of 347 trainees completing the survey reported using Rotterdam criteria to diagnose PCOS. However, only 55% identified Rot-3 and less than 10% identified Rot-5. Seniority (PGY4 OR 2.2; 95% CI: 1.2-4.1; p = .01) and completion of REI rotation (OR 1.8 95% CI: 1.2, 1.8; p = .006) were associated with identifying Rot-3. Similar findings were noted with identifying Rot-5. Our study identified significant gaps in knowledge regarding PCOS, suggesting an urgent need for improving strategies for trainee education to increase patient satisfaction and provide comprehensive care.

Increased odds of disordered eating in polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: We aimed to identify the risk of eating disorders (ED) in women with polycystic ovary syndrome (PCOS) compared to controls. METHODS: We performed a systematic review and meta-analysis of studies that included women with well-defined PCOS and controls and used validated ED screening/diagnostic tools to measure mean ED score, prevalence of abnormal ED scores, and/or prevalence of specific ED diagnoses such as bulimia nervosa and binge eating disorder. RESULTS: Eight studies, including 470 women with PCOS and 390 controls, met inclusion criteria for the systematic review. Meta-analysis of seven of those studies found that the odds of an abnormal ED score (OR 3.05; 95% CI 1.33, 6.99; four studies) and the odds of any ED diagnosis (OR 3.87; 95% CI 1.43, 10.49; four studies) were higher in women with PCOS compared to controls. CONCLUSIONS: Our study suggests that women with PCOS are at increased odds of having abnormal ED scores and specific ED diagnoses. Given the potential implications of an ED on weight management strategies, our findings support routine screening for ED in this population. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis.

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

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups (GDGs), and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (a) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (b) reducing unnecessary testing; (c) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (d) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.

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

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

INTRODUCTION: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non-fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: •Diagnosis:▪when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;▪requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and▪adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.•Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.•Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate.

Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome.

OBJECTIVE: To study the effects of oral contraceptive pills (OCP), the first-line treatment for PCOS, on high-density lipoprotein cholesterol (HDL-C) function (reverse cholesterol efflux capacity) and lipoprotein particles measured using nuclear magnetic resonance spectroscopy in obese women. DESIGN: Secondary analysis of a randomized controlled trial (OWL-PCOS) of OCP or Lifestyle (intensive Lifestyle modification) or Combined (OCP + Lifestyle) treatment groups for 16 weeks. PATIENTS: Eighty-seven overweight/obese women with PCOS at two academic centres. MEASUREMENTS: Change in HDL-C efflux capacity and lipoprotein particles. RESULTS: High-density lipoprotein cholesterol efflux capacity increased significantly at 16 weeks in the OCP group [0·11; 95% confidence interval (CI) 0·03, 0·18, P = 0·008] but not in the Lifestyle (P = 0·39) or Combined group (P = 0·18). After adjusting for HDL-C and TG levels, there was significant mean change in efflux in the Combined group (0·09; 95% CI 0·01, 0·15; P = 0·01). Change in HDL-C efflux correlated inversely with change in serum testosterone (rs = -0·21; P = 0·05). In contrast, OCP use induced an atherogenic low-density lipoprotein cholesterol (LDL-C) profile with increase in small (P = 0·006) and large LDL-particles (P = 0·002). Change in small LDL-particles correlated with change in serum testosterone (rs = -0·31, P = 0·009) and insulin sensitivity index (ISI; rs = -0·31, P = 0·02). Both Lifestyle and Combined groups did not show significant changes in the atherogenic LDL particles. CONCLUSIONS: Oral contraceptive pills use is associated with improved HDL-C function and a concomitant atherogenic LDL-C profile. Combination of a Lifestyle program with OCP use improved HDL-C function and mitigated adverse effects of OCP on lipoproteins. Our study provides evidence for use of OCP in overweight/obese women with PCOS when combined with Lifestyle changes.

High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) have an increased prevalence of moderate and severe depressive and anxiety symptoms compared with control women, and do these symptoms correlate with age, BMI, testosterone, hirsutism or insulin resistance (IR)? SUMMARY ANSWER: Women with PCOS have significantly increased odds of moderate and severe depressive and anxiety symptoms, independent of obesity, and the symptoms are weakly associated with age, BMI, elevated testosterone, hirsutism and IR. WHAT IS KNOWN ALREADY: Previous studies have reported that women with PCOS have an increased prevalence of mild depressive and anxiety symptoms or an increase in mean depression and anxiety scores, although these scores are usually within the normal range. Thus, it is therefore not clear whether these findings are clinically significant. The prevalence of moderate and severe depressive and anxiety symptoms, which require follow-up and would benefit from treatment, is not known in this population. STUDY DESIGN, SIZE, DURATION: A comprehensive systematic review (SR) was performed up to January 2016 and included 30 cross-sectional studies, representing 3050 subjects with PCOS and 3858 controls, from 10 different countries. The meta-analysis (MA) on depressive symptoms included 18 studies and the MA on anxiety symptoms included 9 studies. A separate SR identified 15 studies for the meta-regression examining the associations with PCOS-related symptoms or comorbidities. PARTICIPANTS/MATERIALS, SETTING, METHODS: All studies included adult women with PCOS, defined by the National Institutes of Health or Rotterdam criteria, and a control group without PCOS. Ovid, Embase, PsychInfo and Cochrane were searched up to January 2016. Included studies used a validated screening tool to compare the prevalence or mean scores of depressive and/or anxiety symptoms. Random effects MA was used to estimate the pooled odds ratio (OR) of depressive and anxiety symptoms. Sensitivity analyses of methodological characteristics and a meta-regression of the pooled standardized mean difference (SMD) to evaluate PCOS-related clinical and laboratory associations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had increased odds of any depressive symptoms (OR: 3.78; 95% CI: 3.03-4.72; 18 studies) and of moderate/severe depressive symptoms (OR: 4.18; 95% CI: 2.68-6.52; 11 studies). Women with PCOS had increased odds of any anxiety symptoms (OR: 5.62; 95% CI: 3.22-9.80, nine studies) and of moderate/severe anxiety symptoms (OR: 6.55; 95% CI: 2.87, 14.93; five studies). When subjects were matched on BMI, women with PCOS still had higher odds of both depressive (OR: 3.25; 95% CI 1.73-6.09; four studies) and anxiety symptoms (OR: 6.30, 95% CI: 1.88-21.09; three studies). There was no substantial heterogeneity among studies in the overall MA on depressive symptoms (I2 = 22.4%, P = 0.19), but there was significant heterogeneity among studies in the analysis on anxiety symptoms (I2 = 59.6%, P= 0.01). In the meta-regression evaluating pooled SMDs between groups, women with PCOS and concurrent depression had higher mean values of age, BMI, hirsutism score and IR, while women with PCOS and concurrent anxiety had higher mean values of BMI, hirsutism score and free testosterone (P < 0.05 for all comparisons). LIMITATIONS, REASON FOR CAUTION: All studies were cross-sectional, thus we can only hypothesize that the diagnosis of PCOS precedes the diagnosis of depression and anxiety. There were large variations in methodological characteristics especially in the studies screening for anxiety; however, they only partly explained effect size variation. WIDER IMPLICATIONS OF THE FINDINGS: This evidence-synthesis analysis shows that PCOS diagnosis is associated with an increased risk of moderate and severe depressive and anxiety symptoms and suggests that providers should consider screening women with PCOS for both depression and anxiety. Although age, obesity, hyperandrogenism and IR do not explain the entire association, well-designed studies are needed to assess the impact of treatment of these factors on depressive and anxiety symptoms in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): No funding was used for this study. There are no conflicts of interest. REGISTRATION NUMBER: N/A.

Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study.

BACKGROUND: Polycystic ovary syndrome is a heterogeneous disorder and its presentation varies with race and ethnicity. Reproductive-age women with polycystic ovary syndrome are at increased risk of metabolic syndrome; however, it is not clear if prevalence of metabolic syndrome and clustering of its components differs based on race and ethnicity. Moreover, the majority of these women do not undergo routine screening for metabolic syndrome. OBJECTIVE: We sought to compare the prevalence of metabolic syndrome and clustering of its components in women with polycystic ovary syndrome in the United States with women in India, Brazil, Finland, and Norway. STUDY DESIGN: This is a cross-sectional study performed in 1089 women with polycystic ovary syndrome from 1999 through 2016 in 5 outpatient clinics in the United States, India, Brazil, Finland, and Norway. Polycystic ovary syndrome was defined by the Rotterdam criteria. Main outcome measures were: metabolic syndrome prevalence, blood pressure, body mass index, fasting high-density lipoprotein cholesterol, fasting triglycerides, and fasting glucose. Data from all sites were reevaluated for appropriate application of diagnostic criteria for polycystic ovary syndrome, identification of polycystic ovary syndrome phenotype, and complete metabolic workup. The US White women with polycystic ovary syndrome were used as the referent group. Logistic regression models were used to evaluate associations between race and metabolic syndrome prevalence and its components and to adjust for potential confounders, including age and body mass index. RESULTS: The median age of the entire cohort was 28 years. Women from India had the highest mean Ferriman-Gallwey score for clinical hyperandrogenism (15.6 ± 6.5, P < .001). The age-adjusted odds ratio for metabolic syndrome was highest in US Black women at 4.52 (95% confidence interval, 2.46-8.35) compared with US White women. When adjusted for age and body mass index, the prevalence was similar in the 2 groups. Significantly more Black women met body mass index and blood pressure criteria (P < .001), and fewer met fasting triglycerides criteria (P < .05). The age- and body mass index-adjusted prevalence of metabolic syndrome was highest in Indian women (odds ratio, 6.53; 95% confidence interval, 3.47-12.30) with abnormalities in glucose and fasting high-density lipoprotein cholesterol criterion and in Norwegian women (odds ratio, 2.16; 95% confidence interval, 1.17-3.98) with abnormalities in blood pressure, glucose, and fasting high-density lipoprotein cholesterol criterion. The Brazilian and Finnish cohorts had similar prevalence of metabolic syndrome and its components compared to US White women. CONCLUSION: Despite a unifying diagnosis of polycystic ovary syndrome, there are significant differences in the prevalence of metabolic syndrome and clustering of its components based on race and ethnicity, which may reflect contributions from both racial and environmental factors. Our findings indicate the prevalence of metabolic syndrome components varies in women with polycystic ovary syndrome, such that compared to White women from the United States, Black US women had the highest prevalence, whereas women from India and Norway had a higher prevalence of metabolic syndrome independent of obesity. The differences in clustering of components of metabolic syndrome based on ethnicity highlight the need to routinely perform complete metabolic screening to identify specific targets for cardiovascular risk reduction strategies in these reproductive-age women.

Depression and Anxiety in Polycystic Ovary Syndrome: Etiology and Treatment.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women and is associated with an increased prevalence of depression and anxiety symptoms. This review presents potential mechanisms for this increased risk and outlines treatment options. RECENT FINDINGS: Women with PCOS have increased odds of depressive symptoms (OR 3.78; 95% CI 3.03-4.72) and anxiety symptoms (OR 5.62; 95% CI 3.22-9.80). Obesity, insulin resistance, and elevated androgens may partly contribute to this association. Therefore, in addition to established treatment options, treatment of PCOS-related symptoms with lifestyle modification and/or oral contraceptive pills may be of benefit. Screening for anxiety and depression is recommended in women with PCOS at the time of diagnosis. The exact etiology for the increased risk in PCOS is still unclear. Moreover, there is a paucity of published data on the most effective behavioral, pharmacological, or physiological treatment options specifically in women with PCOS.

GnRH agonist with low-dose hCG (dual trigger) is associated with higher risk of severe ovarian hyperstimulation syndrome compared to GnRH agonist alone.

PURPOSE: The purpose of this study was to compare rates of ovarian hyperstimulation syndrome (OHSS) after using gonadotropin-releasing hormone agonists (GnRHa) alone and GnRHa in combination with low-dose human chorionic gonadotropin (hCG, dual trigger) for final oocyte maturation in women undergoing controlled ovarian hyperstimulation (COH). METHODS: A retrospective cohort study was conducted at an academic center. Study population included 108 women who received GnRHa trigger and 66 women who received dual trigger (GnRHa + low-dose [1000 IU] hCG trigger). The main outcome measure was OHSS. Secondary outcomes included total oocyte yield and oocyte maturity. RESULTS: The incidence of early OHSS was significantly higher after dual trigger than GnRHa trigger (8.6 vs 0 %). Moreover, four of the six patients that developed OHSS developed severe OHSS. Logistic modeling revealed that the combination of age, BMI, baseline AFC, and E2 >4000 pg/mL was predictive of OHSS with an area under the receiver operating characteristic curve of 0.84 and was superior to each factor alone. Adjusted analyses revealed that dual trigger was associated with a higher number of total oocytes (adjusted OR 1.27; 95 % confidence interval, 1.18, 1.38) and percentage of mature oocytes (AOR 1.10; 95 % confidence interval, 1.03, 1.17) obtained compared to GnRHa trigger alone. CONCLUSIONS: Dual trigger for final oocyte maturation using GnRHa and low-dose hCG is associated with a significantly increased risk of severe OHSS compared to GnRH alone. However, dual trigger may be associated with a modest increase in oocyte yield, both in terms of number and maturity.

Mental health disorders-should we screen all our patients?

Understanding the precise interplay between mental and physical health, as related to specific gynecological diseases, is crucial to providing high-quality, comprehensive, and effective care to our patients. A large body of literature provides evidence for the association of infertility, polycystic ovary syndrome, endometriosis and fibroids with anxiety, depression, eating disorders, sexual dysfunction, and/or reduced health related quality of life. Although the precise etiology of these associations is not clear, chronic pain, hormonal changes, body image distress, feelings of helplessness and high stress levels have all been described as possible mediators. Lack of early diagnosis and management of mental health conditions is known to impact compliance with office visits, diagnostic testing and treatment leading to overall reduced quality of life. As part of a holistic approach, we need to develop evidence-based guidelines for screening high-risk patients and increase collaboration between gynecologists and mental health professionals to offer seamless care. This goal may be aspirational as there are several patient- and provider-related challenges to offering comprehensive care to this patient population. Embracing novel technology-based opportunities and incorporating connected healthcare delivery models will help us meet these growing challenges.

Management of polycystic ovary syndrome must include assessment and treatment of mental health symptoms.

Polycystic ovary syndrome (PCOS) is an endocrine disorder with reproductive and metabolic manifestations affecting millions of women worldwide. The health risks associated with PCOS, however, go beyond physical health. Over the past decade, data have emerged demonstrating a high risk of concurrent mental health conditions, specifically depression and anxiety, but extending into other aspects of psychological health, including body image distress, eating disorders, and sexual dysfunction. International surveys suggest physician knowledge about the mental health associations with PCOS is poor and that patients are often dissatisfied regarding counseling-related psychological issues. We performed a review of mental health comorbidities in individuals with PCOS, including depression, anxiety, body image distress, eating disorders, psychosexual dysfunction, and decreased quality of life, as well as evaluated the impact of common PCOS treatments on these conditions. Most meta-analyses in reproductive age women demonstrate increased risks of these conditions, although data are more limited in adolescents and older adults. In addition, the impact of PCOS treatments on these conditions as well as data on first-line treatments in the PCOS population is limited. All providers involved in the multidimensional care of individuals with PCOS should be aware of these mental health risks to provide appropriate screening, counseling and referral options. Future studies should be designed to evaluate targeted treatment for individuals with PCOS.