Context: Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women. Objective: As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin, and combination treatment were evaluated. Data Sources: Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL were searched. Study Selection: Women with PCOS included in randomized controlled trials (RCTs). Data Extraction: We calculated mean differences and 95% CIs regarding anthropometrics, metabolic, and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE were performed. Data Synthesis: The search identified 1660 publications; 36 RCTs were included. For hirsutism, no differences were seen when comparing metformin vs COCP, nor when comparing COCP vs combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08; 95% CI 4.81, 9.36), sex hormone binding globulin (SHBG) (−118.61 nmol/L; 95% CI −174.46, −62.75) and testosterone (0.48 nmol/L; 95% CI 0.32, 0.64) compared with COCP. COCP was inferior for FAI (0.58; 95% CI 0.36, 0.80) and SHBG (−16.61 nmol/L; 95% CI −28.51, −4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (−27.12 pmol/L; 95% CI −40.65, −13.59) and triglycerides (−0.15 mmol/L; 95% CI −0.29, −0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/L; 95% CI 7.79, 26.26) and insulin resistance (0.44; 95% CI 0.17, 0.70) compared with combination treatment. Conclusions: The choice of metformin or COCP treatment should be based on symptoms, noting some biochemical benefits from combination treatment targeting both major endocrine disturbances seen in PCOS (hyperinsulinemia and hyperandrogenism).

Objective: Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines. Design: Systematic review and meta-analysis of the literature. Methods: A search was performed in MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022. Results: Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] −0.53, 95% confidence interval [CI] −0.95 to −0.12 kg/m2), homeostatic model assessment for insulin resistance (MD −0.50, 95% CI −0.91 to −0.09) (critical outcomes), and fasting glucose (MD −0.13, 95% CI −0.19 to −0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74–21.46). Low certainty of evidence showed a larger reduction of waist–hip ratio (MD −0.02, 95% CI −0.03 to −0.00), total cholesterol (MD −0.24, 95% CI −0.43 to −0.05 mmol/L), low-density lipoprotein (MD −0.16, 95% CI −0.30 to −0.01 mmol/L), and triglycerides (MD −0.11, 95% CI −0.20 to −0.02 mmol/L) with metformin than placebo. Conclusions: Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids.

Objectives: To examine the global prevalence of polycystic ovary syndrome (PCOS) among adolescents across world regions, comparing the 2003 Rotterdam consensus criteria with the current International Evidence-based PCOS Guideline criteria which omits polycystic ovarian morphology (PCOM). Design: Systematic review and meta-analysis, Prospero CRD42022372029. Methods: OVID MEDLINE, All EBM, PsycInfo, EMBASE, and CINAHL were searched from 1990 to November 2023 for studies assessing the prevalence of PCOS in unselected adolescent populations. Results: Overall, 15 708 articles were identified. After removal of duplicates, 11 868 titles and abstracts and 445 full texts were assessed. Of these, 24 articles reporting on 23 studies from five world regions were included. In meta-analysis of 20 studies (n = 14 010 adolescents), global prevalence was 9.8% (95% CI 7.2, 12.3) according to original Rotterdam criteria, and 6.3% (95% CI 3.9, 8.8) according to International Evidence-based Guideline criteria. Global PCOS prevalence based on self-report was 9.8% (95% CI 5.5, 14.1). Grouped by WHO region, prevalence ranged from 2.9% (95% CI 2.0, 3.9) in the Western Pacific region to 11.4% (95% CI 7.1, 15.7) in the South-East Asia region according to guideline criteria. Conclusion: This paramount global meta-analysis on adolescent PCOS diagnosis directly informed the 2023 International PCOS Guideline. Guideline criteria generated a global PCOS prevalence of 6.3%, compared with 9.8% on Rotterdam criteria (including PCOM). Excluding PCOM, which overlaps with normal pubertal transition, is expected to deter over-diagnosis. To avoid under-diagnosis, the Guideline recommends identifying those with either irregular cycles or hyperandrogenism as being “at risk”; this group should undergo longitudinal serial evaluations until adulthood.

To compare between different combined oral contraceptive pills (COCP) as part of the update of the International Evidence-Based Guidelines on Assessment and Management of polycystic ovary syndrome (PCOS). Systematic review and meta-analysis, Prospero CRD42022345640 MEDLINE, EMBASE, All EBM, CINAHL and PsycINFO was searched on July 8^th, 2022 for studies including women with PCOS, comparing two different COCPs in randomized controlled trials. 1660 studies were identified,19 RCTs were included. Fourth-generation COCP resulted in lower BMI (MD 1.17 kg/m2 (95% CI 0.33; 2.02) and testosterone (MD 0.60 nmol/L (95% CI 0.13; 1.07) compared with third-generation agents, but no difference was seen in hirsutism. Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone MD 0.38 nmol/L (95%CI 0.33-0.43)) and BMI MD 0.62 kg/m2 (95% CI 0.05-1.20) compared with conventional COCPs. There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified. With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first line COCP treatment by the pending PCOS guideline update, due to higher VTE risk in the general population. Later generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS.

Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy and safety in PCOS remain unclear as previous reviews have focused on non-PCOS populations. To inform the 2023 International Evidence-based Guideline in PCOS, we conducted the first systematic review and meta-analysis investigating the efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS. We systematically searched MEDLINE, Embase, PsycInfo, All EBM reviews, and CINAHL up to 28th June 2023 for randomised controlled trials (RCTs) examining oral anti-androgen use, alone or in combination with metformin, COCPs, lifestyle, or other interventions, in women of any age, with PCOS diagnosed by Rotterdam, National Institutes of Health or Androgen Excess & PCOS Society criteria, and using a form of contraception. Non-English studies and studies of less than 6 months duration or which used the same anti-androgen regimen in both/all groups were excluded in order to establish efficacy for the clinical outcomes of interest. Three authors screened articles against selection criteria and assessed risk of bias and quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Critical outcomes (prioritised during guideline development for GRADE purposes) included weight, body mass index (BMI), irregular cycles, hirsutism, liver function, and quality of life. Random effects meta-analyses were conducted where appropriate. This study is registered with PROSPERO, CRD42022345640. From 1660 studies identified in the search, 27 articles comprising 20 unique studies were included. Of these, 13 studies (n = 961) were pooled in meta-analysis. Seven studies had a high risk of bias, nine moderate and four low. Anti-androgens included finasteride, flutamide, spironolactone, or bicalutamide. In meta-analysis, anti-androgens + lifestyle were superior to metformin + lifestyle for hirsutism (weighted mean difference [WMD] [95% CI]: −1.59 [−3.06, −0.12], p = 0.03; I² = 74%), SHBG (7.70 nmol/l [0.75, 14.66], p = 0.03; I² = 0%), fasting insulin and fasting insulin: glucose ratio (−2.11 μU/ml [−3.97, −0.26], p = 0.03; I² = 0% and −1.12 [−1.44, −0.79], p < 0.0001, I² = 0%, respectively), but were not superior to placebo + lifestyle for hirsutism (−0.93, [−3.37, 1.51], p = 0.45; I² = 76%) or SHBG (9.72 nmol/l [−0.71, 20.14], p = 0.07; I² = 31%). Daily use was more effective for hirsutism than use every three days (−3.48 [−4.58, −2.39], p < 0.0001, I² = 1%), and resulted in lower androstenedione levels (−0.30 ng/ml [−0.50, −0.10], p = 0.004; I² = 0%). Combination treatment with anti-androgens + metformin + lifestyle resulted in lower testosterone compared with metformin + lifestyle (−0.29 nmol/l [−0.52, −0.06], p = 0.01; I² = 61%), but there were no differences in hirsutism when anti-androgens + metformin + lifestyle were compared with either anti-androgens + lifestyle or metformin + lifestyle. In limited meta-analyses (n = 2 trials), combining anti-androgens with COCP resulted in poorer lipid profiles compared with COCP ± placebo, with no differences in other outcomes. Current evidence does not support the use of anti-androgens preferentially to COCPs to treat hyperandrogenism in PCOS. Anti-androgens could be considered to treat hirsutism in PCOS, where COCPs are contraindicated, poorly tolerated, or present a sub-optimal response after a minimum 6-month period, with consideration of clinical context and individual risk factors and characteristics. 10.13039/501100000925 National Health and Medical Research Council (NHMRC) of Australia Monash University.