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Cited by 415Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsGenetic and Kidney Cyst Diseases

Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies

Open access
Cassar, Samantha, Misso, Marie L., Hopkins, William G., Shaw, Christopher S., Teede, Helena J., Stepto, Nigel K.·2016·Human Reproduction
DOI 10.1093/humrep/dew243
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Abstract

STUDY QUESTION: 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? SUMMARY ANSWER: We report an inherent reduction (-27%) of insulin sensitivity (IS) in PCOS patients, which was independent of BMI. WHAT IS ALREADY KNOWN: 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. STUDY DESIGN, SIZE, DURATION: 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%). PARTICIPANTS/MATERIALS, SETTING, METHOD: A total of 4881 articles were returned from the search. Of these, 28 articles were included in the meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTERESTS: 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. REGISTRATION NUMBER: N/A.

Integrity signals

Registry

Crossref · 10.1093/humrep/dew243

Cites

85 of 85 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 43 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Recent genome-wide association studies in Caucasian and Asian PCOS populations report preservation of genes across both NIH and Rotterdam criteria.

    “recent genome-wide association studies in Caucasian (Day et al., 2015;Hayes et al., 2015) and Asian (Chen et al., 2011;Shi et al., 2012) PCOS populations report preservation of genes across both criteria.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Day et al., 2015 source
    • cites Hayes et al., 2015 source
    • cites Chen et al., 2011 source
  • Premisecitation

    The most consistently observed androgenic abnormality in PCOS is elevated free testosterone or calculated free androgen index, which includes SHBG in the equation.

    “The most consistently observed androgenic abnormality in PCOS is elevated 'free testosterone' or calculated free androgen index, which includes SHBG in the equation (Teede et al., 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Teede et al., 2011 source

      The Clinical practice points say calculated free testosterone is a commonly measured marker and that the free androgen index is calculated from testosterone and SHBG. The evidence-based recommendation lists both as first-line tests for biochemical hyperandrogenism in PCOS. Neither passage establishes that their elevation is the most consistently observed androgenic abnormality. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Differences in study or subject characteristics (including inherent problems in analysing and reporting clamp data, recruitment strategies, ethnicity and lifestyle factors) may account for some of the unexplained effects of PCOS on IR.

    “Differences in study or subject characteristics, including inherent problems in analysing and reporting data from the euglycaemic-hyperinsulinaemic clamp, recruitment strategies, ethnicity and lifestyle factors (Day et al., 2015) may account for some of the unexplained effects of PCOS on IR.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Day et al., 2015 source

      The paper discusses heterogeneity among PCOS cases (opening section; no page available) and differences between self-reported and clinically validated recruitment (Discussion; no page available). It does not discuss problems analysing or reporting euglycaemic-hyperinsulinaemic clamp data, or propose ethnicity and lifestyle differences as explanations for unexplained effects of PCOS on insulin resistance. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Findingown data

    A 10-unit higher BMI in women with PCOS is associated with a -28% (±14%; large, most likely) difference in insulin sensitivity.

    “a 10-unit higher BMI in women with PCOS was associated with a -28% (±14%; large, most likely) difference in IS.”
    Quote in the paperSubstantial claim
  • Findingown data

    Total testosterone, when confounding effects of BMI are controlled, has a moderate and very likely effect on insulin resistance.

    “Total testosterone, when the confounding effects of BMI were controlled, had a moderate and very likely effect on IR.”
    Quote in the paperSubstantial claim
  • May combine two claims. 25
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 18

  • May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Three clear outliers were identified; one was corrected and no longer an outlier, and the other two were excluded from the meta-analysis.

    “This approach identified three clear outliers (Micic et al., 2007;Yang et al., 2013;Wu et al., 2014).”
    • Also stated in: § Publication bias and outliers · plain
      “The other two studies were excluded from the meta-analysis (Supplementary Fig. S1).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Micic et al., 2007 source
    • cites Yang et al., 2013 source
    • cites Wu et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Insulin resistance and hyperandrogenism play key roles in the aetiology of PCOS.

    “IR (defined as reduced insulin sensitivity [IS] compared with control women) and hyperandrogenism play key roles in the aetiology (Teede et al., 2007(Teede et al., , 2010)).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Teede et al., 2007 source
    • cites Teede et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Similarities in IR may be related to genetic variations that are preserved across NIH and Rotterdam criteria, suggesting a homogenous disease origin linked to insulin-related genes.

    “Similarities in IR may be related to genetic variations that are preserved across these criteria (Chen et al., 2011;Day et al., 2015;Hayes et al., 2015), suggesting a homogenous disease origin linked to insulin-related genes (Shi et al., 2012).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Chen et al., 2011 source
    • cites Day et al., 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Hayes et al., 2015 source

      The Discussion (page unavailable) reports a PCOS susceptibility locus found in both the NIH-phenotype cohort and a Chinese cohort that included additional Rotterdam phenotypes. It does not link that shared locus to similarities in insulin resistance (IR); it says the NIH phenotype has the highest IR risk and emphasizes gonadotropin-related genes. The sentence cites Shi et al., not Hayes et al., for the separate suggestion about insulin-related genes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Lean and overweight women with PCOS show lower insulin sensitivity compared with their respective controls, with large and very large magnitudes respectively.

    “Compared with their respective controls, lean and overweight women with PCOS showed lower IS with large and very large magnitudes respectively (Table IV, Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Low levels of SHBG are associated with reduced insulin sensitivity (-10%, ±10%; small, very likely negative), not confounded by BMI.

    “Low levels of sex hormonebinding globulin (SHBG) were associated with reduced levels of IS (-10%, ±10%; small, very likely negative), which was not confounded by BMI.”
    • Also stated in: § IS, SHBG and hormone concentrations · plain
      “The mean lower concentration of SHBG in PCOS compared with controls was associated with a small lower IS, which was not confounded by BMI.”
    • Also stated in: § Discussion · boosted
      “SHBG had a strong negative association with IR, which was not confounded by BMI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Younger and older women with PCOS show lower or much lower insulin sensitivity compared with their respective controls (large and very large magnitudes).

    “Compared with their respective controls, younger and older women with PCOS showed lower or much lower IS, respectively (large and very large magnitudes).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    FSH concentrations do not differ between PCOS and controls.

    “FSH concentrations did not differ between PCOS and controls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Increasing age adversely impacts insulin resistance, but the impact is trivial when adjusted for BMI and diagnostic criteria.

    “Increasing age adversely impacted IR, yet the impact was trivial when adjusted for BMI and diagnostic criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Testosterone means are higher in PCOS and are associated with worse insulin sensitivity, but the relationship indicates women with less testosterone are more insulin resistant at the same BMI.

    “Testosterone means were higher in PCOS and were associated with worse IS but the relationship indicates women with less testosterone are more insulin resistant at the same BMI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Older women with PCOS have lower insulin sensitivity compared with younger women with PCOS (large magnitude), but this effect becomes small and unclear when BMI and diagnostic criteria are included in the model.

    “Older women diagnosed with PCOS had a lower IS compared with younger women with PCOS (a large magnitude), but this effect became small and unclear when BMI and diagnostic criteria were included in the model (Table IV).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FSH has a trivial relationship with insulin sensitivity, with only minor differences in FSH concentration between PCOS and control women.

    “while FSH had a trivial relationship with only minor differences in FSH concentration between PCOS and control women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The unexplained residual differences between studies (random effect) were large (~21%) but fell to moderate when all predictors were included in the model.

    “The unexplained residual differences between studies, represented by the random effect, were large (~21%) but fell to moderate, when all predictors were included in the model (Hopkins et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hopkins et al., 2009 source

  • May combine two claims.

    Findingcitation

    SHBG is lower and less variable in PCOS compared with controls.

    “We also confirm that SHBG is not only lower, but also less variable in PCOS, compared with controls (Jayagopal et al., 2003), with larger studies now needed to derive specific SHBG cut-off ranges to predict IR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jayagopal et al., 2003 source

  • May combine two claims.

    Findingown data

    PCOS is associated with intrinsic insulin resistance, with 27% lower insulin sensitivity compared with controls, independent of BMI.

    “We report that PCOS has an intrinsic IR with a 27% lower IS, independent of BMI, with results that are statistically qualitatively 'large' and 'most likely', as defined here.”
    • Also stated in: § Discussion · plain
      “Overall mean -27, ±6 Large****”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PCOS is underpinned by an intrinsic insulin resistance (~27% reduction in insulin sensitivity), independent of BMI and age, as well as across different diagnostic criteria and ethnic groups.

    “Here, we address these gaps and advance the field by confirming in a robust systematic review and meta-analysis, that PCOS is underpinned by an intrinsic IR (~27% reduction in IS), independent of BMI and age, as well as across different diagnostic criteria and ethnic groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Consensus is yet to be achieved in lean women with PCOS because insulin resistance is not consistently demonstrated.

    “Consensus is yet to be achieved in lean women with PCOS as IR is not consistently demonstrated (Diamanti-Kandarakis and Dunaif, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Diamanti-Kandarakis and Dunaif, 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Two independent reviewers scanned the titles, abstracts and keywords of every record retrieved.

    “two independent reviewers scanned the titles, abstracts and keywords of every record retrieved.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Risk of bias of included studies was assessed by a reviewer using criteria developed a priori.

    “Risk of bias of the included studies was assessed by a reviewer using criteria developed a priori (Harris, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Harris, 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Obesity increases circulating androgen and insulin levels, may increase PCOS prevalence, and exacerbates the clinical features of PCOS.

    “Obesity is known to increase circulating androgen and insulin levels, may increase PCOS prevalence and exacerbates the clinical features of PCOS (Fig. 1; Diamanti-Kandarakis and Dunaif, 2012;Teede et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Diamanti-Kandarakis and Dunaif, 2012 source
    • cites Teede et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Insulin resistance and hyperinsulinaemia may directly stimulate production of androgens via ovarian tissue steroidogenesis, independently of changes in gonadotrophin concentration.

    “IR and hyperinsulinaemia may directly stimulate production of androgens via ovarian tissue steroidogenesis, independently of changes in gonadotrophin concentration (Diamanti-Kandarakis and Dunaif, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Diamanti-Kandarakis and Dunaif, 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The systematic review adheres to the principles of the PRISMA guidelines.

    “The systematic review adheres to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.”
    • Also stated in: § Materials and Methods · plain
      “The methodology adheres to the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) Protocols.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The preservation of genes across diagnostic criteria suggests a more homogeneous disease and highlights the need for further research into features such as insulin resistance in women with Rotterdam-diagnosed PCOS.

    “This suggests a more homogeneous disease and highlights the need for further research into features such as IR in women with Rotterdam diagnosed PCOS (Barber et al., 2007;Panidis et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Barber et al., 2007 source
    • cites Panidis et al., 2012 source

  • May combine two claims.

    Study design and conductnone given

    The meta-analysis had an extensive and comprehensive literature search and focused on studies using gold standard methods to measure IR.

    “The strength of this meta-analysis is the extensive and comprehensive literature search and the focus on studies using gold standard methods to measure IR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A meta-analysis cannot solve inherent confounding problems in included studies, which may exaggerate or underestimate effects.

    “A meta-analysis cannot solve inherent confounding problems in included studies, which may exaggerate or underestimate effects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premiseown data

    The current understanding of the interplay between androgens and IR contrasts with the finding that higher androgens are associated with reduced IR.

    “This is in contrast to our current understanding of the interplay between androgens and IR (Diamanti-Kandarakis and Dunaif, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Diamanti-Kandarakis and Dunaif, 2012 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The NIH consensus workshop endorsed the Rotterdam criteria as the definitive diagnostic criteria and recommended that all studies include analyses by reproductive PCOS phenotype.

    “The recent NIH consensus workshop on PCOS endorsed the Rotterdam criteria as the definitive diagnostic criteria (National Institutes of Health, 2012) and recommended that all studies include analyses by reproductive PCOS phenotype.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites National Institutes of Health, 2012

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductnone given

    There was a lack of available robust trials and challenges of extracting reported data from the included studies.

    “There was a lack of available robust trials and challenges of extracting reported data from the included studies as outlined.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Insulin resistance can be measured using numerous direct and indirect techniques, including homeostatic model assessment, quantitative insulin sensitivity check index, and oral glucose tolerance test-related measures comprising area under the curve for glucose and insulin.

    “IR can be measured using numerous direct and indirect techniques, including homeostatic model assessment, quantitative insulin sensitivity check index and oral glucose tolerance test-related measures comprising area under the curve for glucose and insulin (Muniyappa et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Muniyappa et al., 2008 source

  • May combine two claims.

    Premisecitation

    Indirect measures based on fasting or post glucose-load blood glucose and insulin levels lack accuracy and reliability and are inadequate for clinical purposes and mechanistic research where insulin resistance is a primary study outcome.

    “These are based on fasting or post glucose-load blood glucose and insulin levels, yet lack accuracy and reliability and are inadequate for clinical purposes and mechanistic research where IR is a primary study outcome (Muniyappa et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Muniyappa et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Low SHBG levels are increased by insulin-sensitising medication.

    “Low SHBG levels are also increased by insulin-sensitising medication (Ehrmann et al., 1997;Moghetti et al., 2000;Moran et al., 2013);”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ehrmann et al., 1997 source
    • cites Moghetti et al., 2000 source
    • cites Moran et al., 2013 source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Inconsistent reporting of results made it necessary to express variables as factors by dividing the given variable in the PCOS group by that in the respective control group.

    “Inconsistent reporting of results made it necessary to express variables as factors by dividing the given variable in the PCOS group by that in the respective control group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The euglycaemic-hyperinsulinaemic clamp is considered the reference standard to directly measure insulin sensitivity in research settings and can be used to define a specific cut-off level for insulin resistance.

    “The euglycaemic-hyperinsulinaemic clamp is considered the reference standard to directly measure IS in research settings and can be used to define a specific cut-off level for IR (Muniyappa et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Muniyappa et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The inability to acquire missing data from all eligible studies is not unexpected and deemed part of the meta-analysis process.

    “The inability to acquire missing data from all eligible studies is not unexpected and deemed part of the meta-analysis process (Kelley et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kelley et al., 2004 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Low-grade inflammation and sympathetic nervous system dysfunction may influence IR in PCOS.

    “Other key factors may also influence IR in PCOS, including low-grade inflammation (Shorakae et al., 2015) and sympathetic nervous system dysfunction (Diamanti-Kandarakis and Dunaif, 2012;Shorakae et al., 2015) and further research is needed to clarify key mechanisms underpinning IR in PCOS.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Shorakae et al., 2015 source
    • cites Diamanti-Kandarakis and Dunaif, 2012 source

  • May combine two claims.

    Study design and conductnone given

    Small sample sizes and missing data limited evidence synthesis and meta-analysis.

    “Small sample sizes and missing data limited evidence synthesis and meta-analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Endpoints varied (including units and scales).

    “Also endpoints varied (including units and scales).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SHBG concentrations increase with insulin sensitiser treatment.

    “This is consistent with mechanistic studies demonstrating that SHBG production is suppressed by IR and hyperinsulinaemia (Le et al., 2012) and that SHBG concentrations increase with insulin sensitiser treatment (Moghetti et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moghetti et al., 2000 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Not all identified studies were included because of difficulties sourcing the required data from original authors.

    “Furthermore, not all identified studies were included because of difficulties sourcing the required data from original authors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The body of evidence was heterogeneous such that diagnostic criteria were not uniformly applied, with many studies only including women with NIH-diagnosed PCOS and few reporting reproductive phenotypes.

    “The body of evidence was heterogeneous such that diagnostic criteria were not uniformly applied with many studies only including women with NIH-diagnosed PCOS, and few reporting reproductive phenotypes.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    The relationships between BMI and insulin sensitivity and between age and insulin sensitivity are linear in the meta-analytic models.

    “Fixed effects in the model were either linear numeric variables for BMI and age or a nominal variable for the diagnostic criteria (NIH or Rotterdam).”

  • The paper relies on this without support.

    The diagnostic criteria groupings (NIH versus Rotterdam) are valid surrogates for PCOS phenotype.

    “Moderating effects of diagnostic criteria as a surrogate for phenotype”

  • The paper relies on this without support.

    Low SHBG is associated with adverse cardiovascular risk factors, diabetes and metabolic syndrome, independent of obesity.

    “Furthermore, low SHBG is associated with adverse cardiovascular risk factors, diabetes and metabolic syndrome, independent of obesity, all important clinical implications of IR in PCOS, suggesting that SHBG may also be a useful clinical marker of metabolic risk in PCOS.”

  • The paper relies on this without support.

    Little prior PCOS literature has reported by phenotype.

    “However, little prior PCOS literature has reported by phenotype, necessitating analysis here by diagnostic criteria as a proxy.”

  • The paper relies on this without support.

    Prior studies suggest that women with an NIH diagnosis of PCOS are more insulin resistant than those diagnosed via Rotterdam criteria.

    “Prior studies suggest that women with an NIH diagnosis of PCOS are more IR than those diagnosed via Rotterdam criteria.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A systematic review and meta-analysis of euglycemic-hyperinsulinemic clamp studies found that women with PCOS have a 27% reduction in insulin sensitivity compared to BMI and age-matched controls.

    “A systematic review and meta-analysis of euglycemic-hyperinsulinemic clamp studies found that women with PCOS have a 27% reduction in insulin sensitivity compared to body mass index (BMI) and age-matched controls [155].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [155]

    The Abstract reports a 27% lower overall insulin sensitivity in women with PCOS than in controls, and the Conclusion describes this reduction as independent of BMI. However, the Discussion table labels the −27% estimate as unadjusted, while the included-studies table shows differences in age and BMI between some PCOS and control groups. The paper therefore does not establish that the 27% figure specifically compares BMI- and age-matched controls. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • It is likely that all women with PCOS, whether obese or lean, have reduced insulin sensitivity.

    “When the physiology of insulin function is considered to be a quantitative or continuous variable from an evolutionary perspective, it is likely that all women with PCOS, whether obese or lean, have reduced insulin sensitivity [152,155,166].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [155]

    The “Moderating effects of BMI on IS” section (page not available) reports lower insulin sensitivity in both lean and overweight PCOS groups than in their respective controls. This supports the claim across weight groups, but the group-level findings do not establish that every individual woman with PCOS has reduced insulin sensitivity. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The significance of insulin resistance as a pathognomonic component of PCOS is an area of debate.

    “the significance of IR as a pathognomonic component of PCOS is an area of debate [153,154,155].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [155]

    The Introduction says consensus had not been reached on insulin resistance in lean women with PCOS, and the Discussion notes inconsistent earlier data. But the Discussion also says this meta-analysis confirms intrinsic insulin resistance across diagnostic criteria; it does not establish an ongoing debate about whether insulin resistance is a pathognomonic feature. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Central adiposity likely plays a key role in cardiometabolic risk in PCOS.

    “The level of central adiposity likely plays a key role in cardiometabolic risk, as insulin resistance has been associated with higher levels of central adiposity in the PCOS population [32,34,35,36].”

    From Moving beyond Weight: A Narrative Review of the Dietary and Lifestyle Management for Reducing Cardiometabolic Risk in Polycystic Ovary Syndrome (PCOS) (2023) · cites this paper as [32]

    The Discussion (page unavailable) reports that higher BMI exacerbated insulin resistance in PCOS and suggests greater visceral fat as a possible explanation, at least among overweight and obese women. It does not establish an association between measured central adiposity and insulin resistance across the PCOS population, or directly assess cardiometabolic risk. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Hyperinsulinemia and insulin resistance play important roles in the pathophysiology of PCOS for both normal-weight women and women with obesity.

    “Hyperinsulinemia and insulin resistance play important roles in the pathophysiology of PCOS for both normal-weight women and women with obesity (2, 3, 73, 77).”

    From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [3]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Adjusted age effect is called both trivial and small

    Minor

    The discussion calls the BMI- and diagnosis-adjusted age impact trivial, while Table IV labels the corresponding older-versus-younger PCOS effect small and unclear.

  • Conclusion reverses the PCOS and control sample counts

    Minor

    The conclusion assigns 741 participants to PCOS and 1224 to controls; the search-results account assigns those same counts to controls and PCOS, respectively.

  • Adjusted BMI effect has the wrong magnitude label

    Minor

    The paper sets −31% as the threshold for a very large reduction, but labels the adjusted −30% BMI-subgroup effect "Very large." At the reported value, it falls in the large category.

  • Reported age variation is incompatible with the eligibility range

    Minor

    The table gives one group of eight participants a mean age of 25 years and an age SD of 20 years. An SD that large is impossible if every participant was between 18 and 40 years old, as the selection criteria require.

  • Two thresholds are given for a very large improvement

    Minor

    The inferential-statistics section places the very-large improvement threshold at 46%, but the Figure 3 caption places it at 48%.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Yang M . A Review of Random Effects Modelling in SAS (Release 8.2). London: London, Centre for Multilevel Modelling, 2003.

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Related

Authors
Cassar, S., Misso, M. L., Hopkins, W. G., Shaw, C. S., Teede, H. J., & Stepto, N. K.
Affiliations
  • Monash Health (AU)
  • Deakin University (AU)
Corresponding author
Stepto, Nigel K.
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2016-10-07
Volume
31
Issue
11
Pages
2619-2631
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dew243
OpenAlex
W2528179062
Semantic Scholar
7bd1e54cb161a47c607c26284f2c1061e768c318
Cited by
415
References
79
Citations by year
2026: 54 · 2025: 51 · 2024: 59 · 2023: 54 · 2022: 46 · 2021: 42 · 2020: 36 · 2019: 30 · 2018: 22 · 2017: 20 · 2016: 1
FWCI
3.49
Type
journal article
Language
en
Open access
Locations
  • Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
  • Victoria University Research Repository (Victoria University) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Own your potential (DEAKIN) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Australian Government
  • Monash University
  • Medical Research Council
  • National Health and Medical Research Council (606553)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
polycystic ovary syndrome, insulin resistance, insulin sensitivity, body mass index, hyperinsulinemic-euglycemic clamp, PCOS diagnostic criteria, NIH criteria, Rotterdam criteria, sex hormone-binding globulin, hyperandrogenism, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, hyperuricemia, hyperoestrogenism
MeSH terms
Female, Humans, Insulin Resistance, Polycystic Ovary Syndrome, Glucose Clamp Technique, Body Mass Index

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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