Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, 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. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. 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. A (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, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. 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 GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low (n = 1), low (n = 9) and moderate (n = 4) quality with no EBRs based on high-quality evidence. The guideline provides 14 EBRs, 10 clinical consensus recommendations (CCRs) and 20 clinical practice points on the assessment and management of infertility in PCOS. Key changes in this guideline include emphasizing evidence-based fertility therapy, including cheaper and safer fertility management. LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in 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 INTERESTS: 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 (ASRM). GDG 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. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

Metabolic syndrome in polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression.

INTRODUCTION: Women with polycystic ovary syndrome (PCOS) have increased risk of metabolic syndrome. The relative contribution of clinical, demographic or biochemical factors to metabolic syndrome in PCOS is not known. A literature search was conducted in MEDLINE, CINAHL, EMBASE and clinical trial registries. Of 4530 studies reviewed, 59 were included in the systematic review and 27 in the meta-analysis and meta-regression. In good and fair quality studies, women with PCOS had an overall increased prevalence of metabolic syndrome (odds ratio, OR 3.35, 95% confidence interval, CI 2.44, 4.59). Increased prevalence of metabolic syndrome occurred in overweight or obese women with PCOS (OR 1.88, 95% 1.16, 3.04) but not in lean women (OR 1.45, 95% CI 0.35, 6.12). In meta-regression analyses, the markers of metabolic syndrome diagnostic criteria (waist circumference, high-density lipoprotein cholesterol, triglyceride, blood pressure), BMI, glucose tolerance (2-hr oral glucose tolerance test) and surrogate markers of insulin resistance (HOMA-IR) but not markers of reproductive dysfunction (sex hormone binding globulin, testosterone, PCOS phenotypes) contributed significantly to the heterogeneity in the prevalence of metabolic syndrome. Women with PCOS have increased risk of metabolic syndrome which was associated with obesity and metabolic features but not with indices of hyperandrogenism.

Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression.

BACKGROUND: Our prior meta-analyses demonstrated an increased prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) with polycystic ovary syndrome (PCOS), but with substantial clinical heterogeneity. OBJECTIVE AND RATIONALE: We aimed to update our previous review to quantify the prevalence of IGT and T2DM in PCOS with only quality studies (good and fair quality). We also aimed to examine the contribution of parameters including ethnicity, obesity and method of diagnosing T2DM in explaining the observed heterogeneity in IGT and T2DM prevalence in PCOS. SEARCH METHODS: We conducted a literature search (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) up to June 2016 to identify studies reporting the prevalence of dysglycemia (IGT and T2DM) in women with and without PCOS. We included studies where women with PCOS (defined according to original National Institute of Health) were compared to women without PCOS for the end-points of the prevalence of IGT or T2DM. We excluded case reports, case series, editorials, and narrative reviews. Studies where PCOS was diagnosed by self-report, or where IGT or T2DM were measured by fasting glucose, only were excluded. We assessed the methodological quality of the included studies using a priori criteria based on the Newcastle-Ottawa Scaling (NOS) for non-randomized studies. Data are presented as odds ratio (OR) (95% CI) with random-effects meta-analysis by Mantel-Haenszel methods. We assessed the contribution of demographic and clinical factors to heterogeneity using subgroup and meta-regression analysis. OUTCOMES: We reviewed 4530 studies and included 40 eligible studies in the final analysis. On meta-analysis of quality studies, women with PCOS had an increased prevalence of IGT (OR = 3.26, 95% CI: 2.17-4.90) and T2DM (OR = 2.87, 95% CI: 1.44-5.72), which differed by ethnicity (for IGT, Asia: 5-fold, the Americas: 4-fold and Europe: 3-fold), was higher with obesity, and doubled among studies using self-report or administrative data for diagnosing diabetes. The ethnicity-related difference retained its significance for Asia and Europe in BMI-matched subgroups. Clear contributors to heterogeneity did not emerge in meta-regression. WIDER IMPLICATIONS: Our findings underscore the importance of PCOS as a cause of dysglycemia with a higher prevalence of IGT and T2DM. They support the relevance of ethnicity and obesity and emphasize the need for accurate diagnostic methods for diabetes. PROSPERO REGISTRATION NUMBER: CRD42017056524.

Cholesterol feeding prevents adiposity in the obese female aromatase knockout (ArKO) mouse.

The aromatase (ArKO) knockout mouse develops obesity marked by increased gonadal fat depots. This obesity is characterized by pronounced hypertrophy and hyperplasia in adipocytes with corresponding increases in transcripts involved in fat development. Aromatase deficiency in mice and humans with natural mutations of the aromatase gene also leads to metabolic syndrome, particularly hepatic steatosis. In ArKO mice, this hepatic steatosis, the increased body weight and serum triglycerides are surprisingly prevented by cholesterol feeding. We sought to investigate whether the reduction in body weight upon cholesterol feeding is reflected in gonadal fat depots, which account for a large percentage of body weight in the ArKO mouse. Indeed, gonadal fat depots in female ArKO mice were significantly reduced after cholesterol feeding. Concomitantly, adipocyte hyperplasia and hypertrophy were dramatically reduced upon cholesterol feeding in ArKO mice. Real-time PCR analysis revealed concurrent changes with adipocyte volume in the levels of lipoprotein lipase, caveolin-1 and CD59 transcripts. Little change was observed in levels of transcripts involved in de novo fatty acid synthesis, beta-oxidation, lipolysis, differentiation and cholesterol metabolism, suggesting that cholesterol feeding prevents hyperplasia and hypertrophy of ArKO adipocytes, possibly as a consequence of changes in transcript levels of lipoprotein lipase and therefore fatty acid uptake.

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.