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Cited by 334Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsEndometriosis Research and Treatment

Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis

Naderpoor, Negar, Shorakae, Soulmaz, de Courten, Barbora, Misso, Marie L., Moran, Lisa J, Teede, Helena J.·2015·Human Reproduction Update
DOI 10.1093/humupd/dmv025
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Abstract

Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. Methods Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle ± placebo. Results Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, -0.32, P = 0.0005) and subcutaneous adipose ti…

Integrity signals

Registry

Crossref · 10.1093/humupd/dmv025

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 104 cited sources checked · 13 supported · 2 flagged · accuracy not yet measured

  • Findingcitation
    § Metabolic parameters: · p. 8

    At study end (48 weeks), no subjects had IFG or IGT in Hoeger et al. (2004).

    “At study end (48 weeks), no subjects had IFG or IGT (Hoeger et al. , 2004).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hoeger et al. , 2004 source

      The Clinical and Metabolic Parameters passage (page unavailable) reports that two placebo subjects had elevated fasting or two-hour glucose at 48 weeks, contrary to the claim that no subjects did. It reports no such elevations in the three treatment groups, but does not separately classify subjects as having IFG or IGT. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation
    § Introduction · p. 2

    Obesity worsens the hormonal, reproductive, metabolic, and psychological features of PCOS.

    “Obesity further exacerbates hormonal and clinical reproductive, metabolic and psychological features of PCOS (Lim et al. , 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lim et al., 2013 source

      The Principal findings report worse reproductive and metabolic outcomes in obese women with PCOS, with hirsutism as an exception. The Clinical implications section also describes worse psychological features, but the Psychological health section says obesity only appears to contribute and that no included studies reported psychological outcomes. The unqualified claim that obesity worsens psychological features overstates that evidence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Study design and conductnone given
    § Risk of bias · p. 8

    Except for two studies (Hoeger et al., 2004; Gambineri et al., 2006), follow-up duration was 6 months or shorter.

    “Duration of follow-up, except for two studies (Hoeger et al. , 2004; Gambineri et al. , 2006), was 6 months or shorter.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Hoeger et al. , 2004 source
    • cites Gambineri et al. , 2006 source
  • Findingown data
    § Twelve-month outcomes · p. 10

    The number of menstrual cycles from 6 to 12 months was greater in the lifestyle plus metformin group than in the lifestyle plus placebo group (mean difference 1.38, 95% CI 0.47 to 2.29, P=0.003).

    “The number of menstrual cycles from 6 to 12 months was greater in the lifestyle + metformin compared with lifestyle + placebo groups (MD 1.38, 95% CI 0.47-2.29, P ¼ 0.003).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hoeger et al., 2004 source

      The Ovulation section (page not available) reports slightly more menstrual events over the 48-week study in the lifestyle-plus-metformin group than in the lifestyle-plus-placebo group (6.6 versus 6.2). It does not report menstrual-cycle counts specifically from 6 to 12 months or the claimed mean difference, confidence interval, and P value; its finding of no significant difference concerns ovulatory events, not menstrual cycles. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Gambineri et al., 2006 source
  • Findingcitation
    § Secondary outcomes · p. 10

    The remaining four studies did not report significant differences in menstruation between groups (Tang et al., 2006; Karimzadeh and Javedani, 2010; Ladson et al., 2011a, b).

    “The remaining four studies did not report significant differences in menstruation betweengroups (Tang et al. , 2006; Karimzadeh and Javedani, 2010; Ladson et al. , 2011a, b).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Tang et al. , 2006 source
    • cites Karimzadeh and Javedani, 2010 source
    • cites Ladson et al. , 2011a, b

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

  • May combine two claims. 42
  • Classified as probably not a substantial claim. 31
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation
    § Discussion · p. 12

    In people with prior prediabetes or gestational diabetes, metformin lowered weight and BMI.

    “The Indian and US Diabetes Prevention studies, conducted in people with prior prediabetes or gestational diabetes mellitus (GDM) and likely to include many women with PCOS, reported that metformin lowered weight and BMI and reduced progression to DM2 (Knowler et al. , 2002; Ramachandran et al. , 2006), with metformin more effective for women with prior GDM (Ratner et al. , 2008).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Knowler et al. , 2002

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

    • cites Ramachandran et al. , 2006 source

      The Discussion says the IDPP subjects did not lose weight. The Results report no significant change in body weight from baseline in the metformin group; the paper does not report that metformin lowered BMI or establish this outcome in people with prior GDM. It does report reduced progression from impaired glucose tolerance to diabetes. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • The authors state this as an assumption: The Indian and US Diabetes Prevention studies likely included many women with PCOS.

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

    Study design and conductown data
    § Table I Continued · p. 8

    The dropout rate was not reported for one study (Karimzadeh and Javedani, 2010).

    “The dropout rate was not reported for one study (Karimzadeh and Javedani, 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Karimzadeh and Javedani, 2010 source

      The Results and Table 2 report group sizes and pregnancy outcomes, but neither states a dropout rate. Searches for dropout, withdrawal, loss to follow-up, discontinuation, and attrition found no passage addressing whether a dropout rate was reported; the absence of a passage alone does not verify the claim. (LLM, conf=0.70)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Introduction · p. 2

    Lifestyle management is first-line therapy in PCOS for preventing weight gain and for weight loss.

    “Lifestyle management is first line therapy in PCOS for prevention of weight gain and for weight loss (Teede et al. , 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Teede et al., 2011 source

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

    Premisecitation
    § Introduction · p. 2

    Current guidelines indicate metformin in PCOS in some scenarios: to improve fertility, to manage menstrual irregularity when oral contraceptives cannot be used, and in co-existent prediabetes or type 2 diabetes when lifestyle modification fails.

    “Based on current guidelines, metformin is indicated in PCOS in some scenarios to improve fertility (Teede et al. , 2011; Legro et al. , 2013), for management of menstrual irregularity if women are unable to take OCPs, and in co-existent prediabetes or DM2, where lifestyle modification fails (Legro et al. , 2013).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Teede et al., 2011 source
    • cites Legro et al., 2013 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    In PCOS, metformin reduces insulin resistance and inhibits ovarian androgen production through effects on steroidogenic acute regulatory protein and 17alpha-hydroxylase.

    “In PCOS, metformin reduces insulin resistance and inhibits ovarian androgen production via effects on steroidogenic acute regulatory protein and 17alphahydroxylase (Diamanti-Kandarakis et al. , 2010; Viollet et al. , 2012).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Diamanti-Kandarakis et al., 2010

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

    • cites Viollet et al., 2012 source
    • Rests on an assumption: Metformin increases insulin sensitivity by decreasing gluconeogenesis and lipogenesis and by enhancing glucose uptake in the liver, skeletal muscle, adipose tissue, and ovaries.

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

    Premisecitation
    § Introduction · p. 2

    In other populations, metformin prevents weight gain and appears to assist with weight loss, prevents and manages type 2 diabetes, gestational diabetes, and fatty liver, and reduces cardiovascular disease in type 2 diabetes.

    “It is known in other populations to prevent weight gain and appearstoassistwithweightloss,topreventandmanageDM2,gestational diabetes, fatty liver, and reduce cardiovascular disease in DM2 (Lord et al. , 2003; Desilets et al. , 2008; Nestler, 2008; Batra et al. , 2009; NieuwenhuisRuifrok et al. , 2009; Oppelt et al. , 2010; Diabetes Prevention Program Research Group, 2012; Viollet et al. , 2012)”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Lord et al., 2003 source

      The Weight section reports no evidence that metformin reduces weight or BMI in women with polycystic ovary syndrome; it does not assess weight effects in other populations. The Possible recommendations section discusses cardiovascular benefit only as a theoretical possibility in that population. Our copy does not establish the claimed effects on type 2 diabetes, gestational diabetes, fatty liver, or cardiovascular disease in other populations. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites Desilets et al., 2008 source
    • cites Nestler, 2008 source

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

    Premisecitation
    § Introduction · p. 2

    Insulin resistance affects about 85% of PCOS cases, including 75% of lean and 95% of overweight cases.

    “insulin resistance affects ≏ 85% (75% of lean and 95% of overweight) of cases (Stepto et al. , 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Stepto et al., 2013 source

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

    Study design and conductown data
    § Risk of bias · p. 8

    Risk of bias could not be assessed for one study due to insufficient information (Karimzadeh and Javedani, 2010).

    “RoB could not be assessed for one study due to insufficient information (Karimzadeh and Javedani, 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Karimzadeh and Javedani, 2010 source

      The Study Groups section says participants were randomly assigned to four groups but does not describe how assignment was carried out. Neither that section nor the other passages examined state that risk of bias could not be assessed because of insufficient information; that is the citing authors’ assessment, which this source cannot verify. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Insulin resistance and hyperandrogenism are central to the pathophysiology of PCOS.

    “Insulin resistance and hyperandrogenism play a key role in the pathophysiology of PCOS”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Stepto et al., 2013 source

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

    Study design and conductcitation
    § Metabolic parameters: · p. 8

    Insulin resistance was assessed in five of nine studies comparing lifestyle plus metformin with lifestyle plus placebo.

    “Insulin resistance was assessed in five of nine studies comparing lifestyle + metformin with lifestyle + placebo (Pasquali et al. , 2000; Hoeger et al. , 2004; Gambineri et al. , 2006; Ladson et al. , 2011a, b).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Pasquali et al. , 2000 source
    • cites Hoeger et al. , 2004 source
    • cites Gambineri et al. , 2006 source

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    In Hoeger et al., abnormal fasting or 2-hour post-OGTT glucose levels were reported in two subjects on metformin, three on lifestyle, and none on lifestyle plus metformin at baseline.

    “In Hoeger et al. , abnormal fasting or 2 h post OGTT glucose levels were reported in two subjects on metformin, three on lifestyle and none on lifestyle + metforminat baseline.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hoeger et al. , 2004 source

  • May combine two claims.

    Findingcitation
    § Secondary outcomes · p. 10

    In Karimzadeh and Javedani (2010), pregnancy rate was 14% (13/90) on lifestyle plus metformin and 20% (15/75) on lifestyle alone, with no significant difference.

    “It was a secondary outcome in one study (Karimzadeh and Javedani, 2010) with a pregnancy rate of 14% (13/90) on lifestyle + metformin and 20% (15/ 75) on lifestyle alone, with no significant difference.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Karimzadeh and Javedani, 2010 source

      Table 2 reports 13/90 pregnancies in the metformin group and 15/75 in the lifestyle-modification group; the Results say clinical pregnancy rates did not differ significantly (P=.56). The Study Groups section says all participants received diet and exercise advice, but it identifies the 13/90 arm as metformin, not a combined lifestyle-modification-plus-metformin arm. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Findingcitation
    § Secondary outcomes · p. 10

    Two participants on lifestyle plus metformin (16%, 2/12) in Pasquali et al. (2000) became pregnant and were excluded, and two pregnancies (18%, 2/11) occurred on lifestyle plus placebo in Hoeger et al. (2004).

    “Two participants on lifestyle + metformin [16% (2/12)] in one study (Pasquali et al. , 2000) who became pregnant were excluded and two pregnancies [18% (2/11)] occurred on lifestyle + placebo in another study (Hoeger et al. , 2004).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Pasquali et al. , 2000 source
    • cites Hoeger et al. , 2004 source

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

    Findingcitation
    § Metabolic parameters: · p. 8

    At study end, new onset IGT was noted in one subject on metformin and none on lifestyle in Hoeger et al. (2008).

    “At study end, new onset IGT was noted in one subject on metformin and none on lifestyle (Hoeger et al. , 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hoeger et al. , 2008 source

  • Classified as probably not a substantial claim.

    Findingcitation
    § Twelve-month outcomes · p. 10

    Two studies lasting 12 months and 48 weeks provided data on BMI, testosterone, SHBG, FAI, menstruation, fasting glucose, glucose AUC, and insulin AUC.

    “Data on BMI, testosterone, SHBG, FAI, menstruation, fasting glucose, glucose AUC and insulin AUC were also available from two studies with durations of 12 months and 48 weeks (Hoeger et al. , 2004; Gambineri et al. , 2006).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hoeger et al., 2004 source
    • cites Gambineri et al., 2006 source

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    In Hoeger et al. (2008), IFG or IGT was seen in 25% of subjects at baseline (four IFG and six IGT) and one subject had type 2 diabetes, although assignment groups were not noted.

    “In another study by Hoeger et al. (2008), IFG or IGT was seen in 25% of subjects at baseline (four IFG and six IGT) and one subject had DM2, although assignment groups were not noted.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hoeger et al. , 2008 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Discussion · p. 13

    Metformin reduces insulin resistance in type 2 diabetes and in adults and adolescents with PCOS when hyperinsulinaemic euglycaemic clamps are used.

    “Metformin clearly reduces insulin resistance in DM2and in adults and adolescents with PCOS when hyperinsulinaemic euglycaemic clamps were used (Moghetti et al. , 2000; Meyer et al. , 2007; Arslanian et al. , 2002).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Moghetti et al. , 2000 source
    • cites Meyer et al. , 2007 source
    • cites Arslanian et al. , 2002 source

      The Results (p. 3) report significantly higher insulin-stimulated glucose disposal after metformin treatment, measured with a hyperinsulinemic-euglycemic clamp in obese adolescents with PCOS and impaired glucose tolerance. This study did not test adults with PCOS or people with type 2 diabetes. The Discussion (p. 4) also cautions that, because the trial was open-label, the observed effects cannot be attributed to metformin with certainty. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Discussion · p. 13

    Recent literature suggests a possible dose-dependent effect of metformin on vitamin B12 absorption, though it is often not clinically significant.

    “Emerging literature including a recent systematic review is suggestive of a possible dose dependent effect of metformin on vitamin B12 absorption (Liu et al. , 2014), although this is often not clinically significant.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Liu et al. , 2014 source

      The Results report that vitamin B12 concentration fell more in the higher-dose than the lower-dose metformin group. The Discussion proposes malabsorption as a possible mechanism, but the review does not establish a dose-dependent effect on absorption itself. It describes the clinical significance of lower B12 concentrations as controversial, rather than establishing that the effect is often not clinically significant. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Discussion · p. 12

    Current guidelines recommend using metformin in obese women with PCOS who have prediabetes or type 2 diabetes.

    “In the interim there is inadequate evidence on the impact of metformin on glucose tolerance in prediabetes and DM2 specifically in PCOS, but based on data in general populations, current guidelines recommend using metformin in obese women with PCOS who have prediabetes or DM2 (Legro et al. , 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Legro et al. , 2013 source

      The guideline’s ‘Use of metformin in adults’ recommendation (3.6; page not provided) recommends metformin for women with PCOS and type 2 diabetes or impaired glucose tolerance, but only if lifestyle modification fails. It does not limit that recommendation to obese women, and the claim omits the lifestyle-modification condition. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

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

    Findingown data
    § Study selection · p. 4

    Mean BMI was greater than 35 kg/m2 in 7 of the 12 randomized controlled trials.

    “MeanBMIwas . 35 kg/m 2 in 7 of 12 RCTs (Pasquali et al. , 2000; Hoeger et al. , 2004, 2008; Gambineri et al. , 2006; Tang et al. , 2006; Ladson et al. , 2011a, b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § table of contents · p. 2

    The review identified 2372 studies and included 12 randomized controlled trials with a total of 608 women with PCOS in the meta-analysis.

    “Of2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS.”
    • Also stated in: § Study selection · p. 4 · plain
      “Twelve RCTs met the inclusion criteria”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § table of contents · p. 2

    In women with PCOS, metformin alone compared with lifestyle plus placebo lowers testosterone after 6 months.

    “but testosterone was lower with metformin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Study selection · p. 4

    Interventions ranged from 3 to 12 months, with 608 participants aged 12 to 39 years across the lifestyle plus metformin, lifestyle plus placebo, or metformin alone arms.

    “Interventions ranged from 3 to 12 months with a total of 608 participants aged 12-39 years in lifestyle + metformin or lifestyle + placebo or metformin alone arms of RCTs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    In the study not included in the meta-analysis due to shorter duration (Otta et al., 2010), lifestyle plus metformin was associated with lower fasting insulin and HOMA compared with baseline, but these differences were not statistically significant compared with lifestyle plus placebo.

    “In the study not included in the meta-analysis due to shorter duration (Otta et al. , 2010), lifestyle + metformin was associated with lower fasting insulin and HOMA compared with baseline, but these differences were not statistically significant compared with lifestyle + placebo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Otta et al. , 2010

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

  • May combine two claims.

    Findingown data
    § Secondary outcomes · p. 8

    There were no differences in visceral and total adipose tissue, waist circumference, or WHR at study end for lifestyle plus metformin compared with lifestyle plus placebo.

    “There were no differences in visceral and total adipose tissue, waist circumference and WHR (Table III) at study end for lifestyle + metformin compared with lifestyle + placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    None of the women on lifestyle plus metformin and two on lifestyle plus placebo required additional insulin treatment in Vanky et al. (2004).

    “None of the women on lifestyle + metformin and two on lifestyle + placebo required additional insulin treatment (Vanky et al. , 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vanky et al. , 2004

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

  • May combine two claims.

    Findingown data
    § Secondary outcomes · p. 8

    There were no differences in biochemical hyperandrogenism, acne, or Ferriman-Gallwey score for hirsutism at study end for lifestyle plus metformin compared with lifestyle plus placebo.

    “There were no differences in biochemical hyperandrogenism, acne or Ferriman-Gallwey score for hirsutism (Table III) at study end for lifestyle + metformin compared with lifestyle + placebo studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    In Gambineri et al. (2006), IGT was seen in three (15%) subjects on lifestyle plus metformin and two (11%) on lifestyle plus placebo at baseline, decreasing to two (10%) and 0 respectively at 12 months.

    “In addition, IGT was seen in three (15%) subjects on lifestyle + metformin and two (11%) on lifestyle + placebo at baseline which decreased to two (10%) and 0 respectively at 12 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gambineri et al. , 2006 source

  • May combine two claims.

    Findingcitation
    § Metabolic parameters: · p. 8

    In Otta et al., one subject on lifestyle plus metformin and five on lifestyle plus placebo were prediabetic (no definition provided) at baseline, and all normalized by study end (4 months).

    “In Otta et al. , one subject on lifestyle + metformin and five on lifestyle + placebo were prediabetic (no definition provided) at baseline and all normalized by study end (4 months) (Otta et al. , 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Otta et al. , 2010

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

  • May combine two claims.

    Findingown data
    § Metabolic parameters: · p. 8

    There were no significant differences in post-OGTT insulin AUC, fasting insulin, insulinogenic index, insulin sensitivity index, or QUICKI at study completion between lifestyle plus metformin and lifestyle plus placebo.

    “There were no significant differences in post OGTT insulin (insulin AUC) (MD 0.18 m U/ml/min, 95% CI 2 0.18, 0.55, P 0.31) (Fig. 4), fasting insulin, insulinogenic index, insulin sensitivity index and QUICKI (Table III) at study completion between lifestyle + metformin groups compared with lifestyle + placebo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Secondary outcomes · p. 10

    There were no differences in fasting glucose, glucose AUC, lipids, or blood pressure at study end for lifestyle plus metformin versus lifestyle plus placebo.

    “Therewerenodifferences in fasting glucose (Fig. 7), glucoseAUC,lipidsorbloodpressure(TableIII)atstudyendforlifestyle + metformin versus lifestyle + placebo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Secondary outcomes · p. 10

    In Tang et al. (2006), pregnancy rates were 8.7% (6/69) on lifestyle plus metformin and 2.7% (2/74) on lifestyle plus placebo, with no significant difference.

    “In another study with participants who all desired pregnancy, pregnancy rates were 8.7% (6/69) on lifestyle + metformin and 2.7% (2/74) on lifestyle + placebo, with no significant difference (Tang et al. , 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tang et al. , 2006 source

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Obesity and PCOS have a bidirectional relationship: obesity increases PCOS prevalence and PCOS increases weight gain and obesity.

    “EmergingdatasuggestobesityhasabidirectionalrelationshipwithPCOS, with obesity increasing PCOS prevalence and PCOS increasing weight gain and obesity (Teede et al. , 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Teede et al., 2013 source

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Hyperinsulinaemia increases androgen production and reduces sex hormone-binding globulin, leading to hyperandrogenism.

    “The resulting hyperinsulinaemia increases androgen production and reduces sex hormone-binding globulin (SHBG) leading to hyperandrogenism (Teede et al. , 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Teede et al., 2007 source

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Overweight and obesity, which are common in PCOS, further exacerbate insulin resistance.

    “Insulin resistance is further exacerbated by overweight and obesity, a commonfinding in PCOS [risk ratio (95% confidence interval (CI)): 1.95 (1.52, 2.50) and 2.77 (1.88, 4.10), respectively, for women with PCOS compared with controls from a systematic review] (Ng et al. , 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ng et al., 2014

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

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

    Study design and conductnone given
    § Table I Continued · p. 8

    Participants with type 2 diabetes but not glucose intolerance were excluded before randomization in all studies except one (Hoeger et al., 2008).

    “Participants with DM2 but not glucose intolerance were excluded before randomization in all studies except for one (Hoeger et al. , 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoeger et al. , 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Data synthesis and meta-analysis · p. 4

    An I2 value greater than 30% was considered moderate to high heterogeneity.

    “I 2 . 30% was considered as moderate to high heterogeneity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data
    § Risk of bias · p. 8

    There was one study with high risk of bias, seven with moderate risk, and three with low risk.

    “There was one study with high RoB, seven studies with moderate and three with low RoB.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Risk of bias appraisal · p. 4

    The review assessed the methodological quality of included studies using a risk-of-bias tool developed a priori.

    “To assess the methodological quality of the included studies, a risk of bias (RoB) assessment tool developed a priori was employed.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning
    § Study selection · p. 4

    Results from one study involving pregnant women with PCOS were excluded from the meta-analysis to reduce heterogeneity.

    “Results from one study that involved pregnant womenwithPCOSwerenotincludedinthemeta-analysistoreduceheterogeneity.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Data extraction · p. 4

    Data were extracted from included studies by two independent reviewers using a specially developed data extraction form.

    “Data were extracted from included studies by two independent reviewers (N.N., S.S.) using a specially developed data extraction form according to the selection criteria.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given
    § Introduction · p. 2

    Key knowledge gaps remain regarding the efficacy of metformin and its specific role in PCOS, including in weight management.

    “However key knowledge gaps remain on the efficacy of metformin and its specific role in PCOS, including in weight management.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given
    § table of contents · p. 2

    The included studies have limitations including small sample sizes, short durations, and risk of bias.

    “Existing study limitations include small sample sizes, short durations and risk of bias.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data
    § Table I Continued · p. 8

    The dropout rate was 25% (71/279) for lifestyle plus metformin or metformin alone and 29% (79/271) for lifestyle plus placebo.

    “The dropout rate was 25% (71/279) for lifestyle + metformin or metformin alone treatment and 29% (79/271) for lifestyle + placebo treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning
    § Study selection · p. 4

    Six-month data were selected for meta-analysis because most studies were 6 months and 6-month data were available for the two longer 48- and 52-week studies.

    “Most studies were for 6 months and 6-month data were also available for the two longer 48- and 52-week studies. Six-month data were therefore selected for meta-analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Weight loss through lifestyle modification, medications, or bariatric surgery improves insulin resistance, reduces hyperandrogenism, and alleviates PCOS clinical severity.

    “Consistently, weight loss through lifestyle modification (comprising dietary modification, physical activity and/or behavioural change), medications (metformin, orlistat, incretin mimetics) orbariatric surgery improves insulin resistance, reduces hyperandrogenism and alleviates PCOS clinical severity (Moran et al. , 2011; Vosnakis et al. , 2013; Jensterle et al. , 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Moran et al., 2011 source
    • cites Vosnakis et al., 2013 source
    • cites Jensterle et al., 2015 source

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

    Study design and conductreasoning
    § Data synthesis and meta-analysis · p. 4

    A fixed-effect model was used for variables with low heterogeneity, and a random-effect model was used for variables with moderate or high heterogeneity.

    “The fixed-effect model was used for variables with low heterogeneityandtherandom-effectmodelwasusedforvariableswithmoderate or high heterogeneity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given
    § Risk of bias · p. 8

    None of the authors had a conflict of interest.

    “None of the authors had a conflict of interest.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given
    § Risk of bias · p. 8

    The specified methods of measurement for these variables were all standard and reliable.

    “The specified methods of measurement for these variables were all standard and reliable.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation
    § Secondary outcomes · p. 8

    Body composition as assessed by computed tomography at L4-5 was provided in two of nine studies comparing lifestyle plus metformin with lifestyle plus placebo.

    “Body composition as assessed by computed tomography(CT)atL4-5wasprovided in two (Pasquali et al. , 2000; Gambineri et al. , 2006) of nine studies comparing lifestyle + metformin with lifestyle + placebo.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pasquali et al. , 2000 source
    • cites Gambineri et al. , 2006 source

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

    Study design and conductown data
    § Secondary outcomes · p. 8

    Menstruation was assessed in seven of nine studies comparing lifestyle plus metformin with lifestyle plus placebo.

    “Menstruationwasassessedinsevenofninestudiescomparinglifestyle + metformin with lifestyle + placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data
    § Risk of bias · p. 8

    Main reasons for higher risk of bias included lack of blinding of outcome assessors, not applying intention-to-treat analysis, and high dropout rates.

    “Main reasons for higher RoBincludelackof blinding of outcome assessors (detection bias), not applying intention to treat analysis, and high dropout rates (Table II).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Metabolic parameters: · p. 8

    A meta-analysis was not performed on HOMA due to small study numbers (n=2).

    “A meta-analysis was not performed on HOMA due to small study numbers ( n ¼ 2).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Secondary outcomes · p. 8

    Two studies using dual-energy X-ray absorptiometry for body composition could not be included in meta-analysis because one reported mean change and the other only end results.

    “Twostudies that used dual-energy X-ray absorptiometry (DEXA) for body composition could not be included for meta-analysis as one reported mean change and the other reported only the end result.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Discussion · p. 13

    The review was limited to articles published in English and most included studies had moderate risk of bias.

    “This review was also limited to articles published in English and most had moderate RoB.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Discussion · p. 11

    Women with PCOS report significant concern regarding weight gain.

    “Womenwith PCOS report significant concern regarding weight gain, havehigherratesofweightgainandaremorelikelytobeobese(Lim et al. ,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lim et al.

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

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

    Study design and conductnone given
    § Discussion · p. 13

    The review's strengths include the novelty of comparing combined lifestyle plus metformin with lifestyle plus placebo and its comprehensive systematic review and meta-analysis methodology.

    “The strengths of this review are the novelty of the clinically relevant comparison of combined lifestyle + metformin with lifestyle + placebo and the comprehensive systematic review and meta-analysis methodology.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion · p. 11

    Women with PCOS have higher rates of weight gain.

    “Womenwith PCOS report significant concern regarding weight gain, havehigherratesofweightgainandaremorelikelytobeobese(Lim et al. ,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lim et al.

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

  • May combine two claims.

    Interpretationown data
    § Conclusion · p. 13

    Lifestyle plus metformin appears to offer benefits in weight loss and menstrual cyclicity.

    “Here, in the first systematic review and meta-analysis to explore the addition of metformin to lifestyle versus lifestyle + placebo, we report that lifestyle + metformin appears to offer benefits in weight loss and menstrual cyclicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion · p. 13

    Almost all participants were obese, limiting generalizability to lean PCOS women, and phenotypic subgroups were not identified.

    “Almost all participants in this review were obese, limiting generalizability of these findings to lean PCOS women, and phenotypic subgroups were not identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion · p. 13

    Lactic acidosis is an exceptionally rare complication of metformin that occurs with serious comorbidities including renal insufficiency.

    “Lactic acidosis is an exceptionally rare complication that occurs in the setting of serious comorbidities including renal insufficiency (Baileyand Turner, 1996; DeFronzo, 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baileyand Turner, 1996

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

    • cites DeFronzo, 2000 source

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

    Premisecitation
    § Discussion · p. 11

    Women with PCOS are more likely to be obese.

    “Womenwith PCOS report significant concern regarding weight gain, havehigherratesofweightgainandaremorelikelytobeobese(Lim et al. ,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lim et al.

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

  • May combine two claims.

    Interpretationown data
    § Conclusion · p. 13

    Metformin may have a key role in PCOS, in addition to lifestyle, to assist in weight management and cycle regulation.

    “we suggest that metformin may have a key role in PCOS, in addition to lifestyle, to assist in weight management and cycle regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given
    § Discussion · p. 11

    Most studies had small sample sizes and moderate to high risk of bias.

    “most studies had small sample sizes and moderate to high RoB.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data
    § Discussion · p. 13

    The review identified a limited number of RCTs, most with small sample sizes, high attrition, and poor adherence.

    “However we report a limited number of identified RCTs, with most involving small sample sizes, high attrition rates and poor adherence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Discussion · p. 13

    Metformin could be a safe choice of medication if its efficacy in PCOS is confirmed.

    “Therefore, metformin could be a safe choice of medication, should its efficacy in PCOS be confirmed.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The most common metformin side effects are mild and transient and may be reduced by taking the medication with food or gradually escalating the dose.
66 of 66

  • The paper relies on this without support.

    Metformin increases insulin sensitivity by decreasing gluconeogenesis and lipogenesis and by enhancing glucose uptake in the liver, skeletal muscle, adipose tissue, and ovaries.

    “Metforminincreases insulin sensitivity by decreasing gluconeogenesis, lipogenesis and enhancing glucose uptake in the liver, skeletal muscle, adipose tissue and ovaries.”

  • The paper relies on this without support.

    Engagement, compliance, and sustainability with lifestyle modification in PCOS remain challenging.

    “While evidence-based guidelines recommend lifestyle modification as first line treatment in PCOS (Teede et al. , 2011), engagement, compliance and sustainability remain challenging.”

  • The paper relies on this without support.

    The most common metformin side effects are mild and transient and may be reduced by taking the medication with food or gradually escalating the dose.

    “The most common side effects of metformin are appetite suppression, nausea or vomiting, abdominal bloating and diarrhoea that are often mild and transient and may be reduced by taking the medication with food or gradually escalating the dose.”

  • The paper relies on this without support.

    PCOS is closely related to obesity and weight management is first-line therapy.

    “PCOS is closely inter-related to obesity and weight management is first line therapy.”

  • The authors state this as an assumption.

    The Indian and US Diabetes Prevention studies likely included many women with PCOS.

    “The Indian and US Diabetes Prevention studies, conducted in people with prior prediabetes or gestational diabetes mellitus (GDM) and likely to include many women with PCOS, reported that metformin lowered weight and BMI and reduced progression to DM2 (Knowler et al. , 2002; Ramachandran et al. , 2006), with metformin more effective for women with prior GDM (Ratner et al. , 2008).”
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?

Self-check

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

  • Gambineri dropout percentage conflicts with its fraction

    Minor

    Table II reports one dropout among ten participants as 5%; one out of ten is 10%.

    Reported 5 · recomputed 10

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. NEbw panel. NIH Evidence based workshop on Polycystic Ovary Syndrome. 2012.

Cited by

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Related

Authors
Naderpoor, N., Shorakae, S., de Courten, B., Misso, M. L., Moran, L. J., & Teede, H. J.
Affiliations
  • Monash Health (AU)
  • Monash University (AU)
Corresponding author
Teede, Helena J.
ORCID
Venue
Human Reproduction Update
Publisher
Oxford University Press (OUP)
Published
2015-06-09
Volume
21
Issue
5
Pages
560-574
ISSN
  • 1355-4786 (ISSN-L)
  • 1460-2369
DOI
10.1093/humupd/dmv025
OpenAlex
W4244088697
Cited by
334
References
65
Citations by year
2026: 16 · 2025: 25 · 2024: 24 · 2023: 45 · 2022: 34 · 2021: 40 · 2020: 27 · 2019: 37 · 2018: 24 · 2017: 31 · 2016: 25 · 2015: 6
FWCI
4.31
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction Update (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • NHMRC
  • SACVRDP
  • South Australian Department of Health and the South Australian Health and Medical Research Institute
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
Keywords
polycystic ovary syndrome, metformin, lifestyle modification, insulin resistance, obesity, body mass index, menstrual cyclicity, ovulation, hyperandrogenism, testosterone, quality of life, weight loss, subcutaneous adipose tissue, hyperinsulinemia, lipid profile, blood pressure, psychological outcomes, reproductive outcomes, metabolic outcomes, medication adherence, treatment sustainability
MeSH terms
Combined Modality Therapy, Female, Humans, Hyperinsulinism, Hypoglycemic Agents, Insulin Resistance, Metformin, Obesity, Ovulation, Polycystic Ovary Syndrome, Quality of Life, Randomized Controlled Trials as Topic, Hyperandrogenism, Risk Reduction Behavior

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 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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