title: Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies.
abstract: What is the degree of intrinsic insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) and the relative contribution of BMI to overall IR based on meta-analysis of gold standard insulin clamp studies?
  
  
  
  We report an inherent reduction (-27%) of insulin sensitivity (IS) in PCOS patients, which was independent of BMI.
  
  
  
  PCOS is prevalent, complex and underpinned by IR but controversies surround the degree of intrinsic IR in PCOS, the effect of BMI and the impact of the different diagnostic criteria (NIH versus Rotterdam) in PCOS.
  
  
  
  A systematic review and meta-analysis of Medline and All EBM databases was undertaken of studies published up to 30 May 2015. Studies were included if premenopausal women diagnosed with PCOS were compared with a control group for IS, measured by the gold standard euglycaemic-hyperinsulinaemic clamp. The systematic review adheres to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analyses were performed using mixed modelling and magnitude-based inferences expressed as mean effect ±99% CI. We inferred the effect was small, moderate or large relative to a smallest important change of -3.7% or 3.8% derived by standardisation. Effects were deemed unclear when the CI overlapped smallest important positive and negative values. Effects were qualified with probabilities reflecting uncertainty in the magnitude of the true value (likely, 75-95%; very likely, 95-99.5%; most likely, >99.5%).
  
  
  
  A total of 4881 articles were returned from the search. Of these, 28 articles were included in the meta-analysis.
  
  
  
  Overall IS was lower in women with PCOS compared with controls (mean effect -27%, 99% CI ±6%; large, most likely lower). A higher BMI exacerbated the reduction in IS by -15% (±8%; moderate, most likely lower) in PCOS compared with control women. There was no clear difference in IS between women diagnosed by the original National Institutes of Health  (NIH) criteria alone compared with those diagnosed by the Rotterdam criteria. Low levels of sex hormone-binding globulin (SHBG) were associated with reduced levels of IS (-10%, ±10%; small, very likely negative), which was not confounded by BMI.
  
  
  
  This systematic review and meta-analysis inherited the confounding problems of small sample sizes, missing data (e.g. some hormones, waist and hip girths) and the lack of Rotterdam criteria phenotype reporting, limiting the evidence synthesis and meta-analysis.
  
  
  
  BMI has a greater impact on IS in PCOS than in controls. SHBG appears a potentially valuable marker of IR in PCOS, whereas testosterone after adjustment for BMI demonstrated an unexpected interplay with IS which warrants further investigation.
  
  
  
  This work was supported by grants from the National Health & Medical Research Council (NHMRC), grant number 606553 (H.J.T., N.K.S.), as well as Monash University. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Government's Collaborative Research Networks (CRN) programme. The funding bodies played no role in the design, methods, data management or analysis or in the decision to publish. All authors declare no conflict of interests.
  
  
  
  N/A.
authors.affiliation: Institute of Sport Exercise and Active Living, College of Sport and Exercise Science, Victoria University, PO Box 14428, Melbourne, Victoria, 8001, Australia.|Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University in Partnership with Monash Health, Locked Bag 29, Clayton, Victoria 3168, Australia.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cassar
authors.affiliation: Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University in Partnership with Monash Health, Locked Bag 29, Clayton, Victoria 3168, Australia.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Misso
authors.affiliation: Institute of Sport Exercise and Active Living, College of Sport and Exercise Science, Victoria University, PO Box 14428, Melbourne, Victoria, 8001, Australia.
authors.forename: William G
authors.initials: WG
authors.lastname: Hopkins
authors.affiliation: Institute of Sport Exercise and Active Living, College of Sport and Exercise Science, Victoria University, PO Box 14428, Melbourne, Victoria, 8001, Australia.|Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3126, Australia.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Shaw
authors.affiliation: Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University in Partnership with Monash Health, Locked Bag 29, Clayton, Victoria 3168, Australia.|Diabetes and Vascular Medicine Unit, Monash Health, 246 Clayton Road, Clayton, Victoria, 3168, Australia.
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Teede
authors.affiliation: Institute of Sport Exercise and Active Living, College of Sport and Exercise Science, Victoria University, PO Box 14428, Melbourne, Victoria, 8001, Australia nigel.stepto@vu.edu.au.|Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University in Partnership with Monash Health, Locked Bag 29, Clayton, Victoria 3168, Australia.
authors.forename: Nigel K
authors.initials: NK
authors.lastname: Stepto
mesh_terms: D015992:Body Mass Index; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D011085:Polycystic Ovary Syndrome / Q000378:metabolism*
keywords: FSH; LH; magnitude-based inferences; sex hormone-binding globulin; testosterone