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Cited by 72Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsEndometriosis Research and Treatment

The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials

Open access
Melin, Johanna, Forslund, Maria, Alesi, Simon, Piltonen, Terhi, Romualdi, Daniela, Spritzer, Poli Mara, Tay, Chau Thien, Pena, Alexia +3 more·2023·European Journal of Endocrinology
DOI 10.1093/ejendo/lvad098
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Abstract

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

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis of 32 RCTs found that metformin, with or without lifestyle modification, improved several anthropometric and metabolic outcomes versus placebo in PCOS, especially in adults with BMI ≥25 kg/m². It informed the 2023 International PCOS Guideline, with mild gastrointestinal adverse effects more common with metformin.

Key findings

  • Metformin vs placebo showed moderate-certainty reductions in BMI (MD −0.53 kg/m², 95% CI −0.95 to −0.12), HOMA-IR (MD −0.50, 95% CI −0.91 to −0.09), and fasting glucose (MD −0.13 mmol/L, 95% CI −0.19 to −0.07), with increased mild gastrointestinal adverse effects (OR 7.67, 95% CI 2.74–21.46).
  • Low-certainty reductions vs placebo were found for WHR (MD −0.02), total cholesterol (MD −0.24 mmol/L), LDL (MD −0.16 mmol/L), and triglycerides (MD −0.11 mmol/L); very-low-certainty reductions were found for total testosterone (MD −0.47 nmol/L), CRP (MD −3.51 nmol/L), PAI-1 (MD −4.99 ng/mL), and menstrual cycle length (MD −38.25 days).
  • In BMI ≥25 kg/m² subgroups, metformin reduced BMI (MD −0.89 kg/m², 95% CI −1.43 to −0.35), fasting glucose (MD −0.13 mmol/L), total cholesterol (MD −0.41 mmol/L), and LDL (MD −0.35); in BMI <25 kg/m², reductions were seen for WHR (MD −0.01), FAI (MD −1.01), and androstenedione (MD −5.40 nmol/L).
  • Metformin plus lifestyle vs placebo plus lifestyle lowered BMI (MD −1.09 kg/m², 95% CI −2.12 to −0.06) and increased mild gastrointestinal adverse effects (OR 3.28, 95% CI 1.64–6.57); metformin vs lifestyle showed no BMI difference, metformin lowered testosterone (MD −0.17 nmol/L), and lifestyle improved SHBG (MD −10.73 nmol/L), all very low certainty.

Methods

  • Systematic review and meta-analysis following PRISMA, registered in PROSPERO (CRD42022345640); searched MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL through 7 July 2022, limited to English-language RCTs.
  • Included 32 RCTs (29 adult, 3 adolescent; 14 Europe, 6 North America, 4 South America, 8 Middle East); metformin dose ranged from 850 to 2000 mg/day; follow-up ranged from 3 to 7 months.
  • Random-effects meta-analyses in Review Manager 5.4 reported MDs for continuous outcomes and ORs for dichotomous outcomes with 95% CIs; subgroup analyses by BMI <25 vs ≥25 kg/m²; risk of bias assessed with adapted RoB2 and certainty with GRADE.

Limitations

  • The paper states: absence of larger studies in women with BMI <25 kg/m² and adolescents; language bias from excluding non-English studies; critical appraisal is subjective though double-checked; low or very low certainty for some outcomes due to poorly described randomization or lack of blinding; adverse effects were not systematically reported.
  • The text also makes evident that some analyses relied on small subgroups (e.g., BMI <25 kg/m² comparisons with 70 vs 69 participants altogether) and that heterogeneity from differing metformin doses and treatment durations was addressed with a random-effects model.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/ejendo/lvad098

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 45 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Metformin compared to placebo produced a larger reduction in WHR (MD -0.02, 95% CI -0.03 to -0.00), with low certainty.

    “the reduction of WHR (MD -0.02, 95% CI -0.03 to -0.00) (low certainty)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Metformin was superior to lifestyle in lowering testosterone (MD -0.17, 95% CI -0.31 to -0.03 nmol/L).

    “Metformin was superior in lowering testosterone (MD -0.17, 95% CI -0.31 to -0.03 nmol/L)”
    Quote in the paperSubstantial claim
  • Findingown data

    Metformin compared to placebo produced a larger reduction in triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L), with low certainty.

    “triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L) (low certainty)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Participants with lifestyle only had improved SHBG compared to metformin (MD -10.73, 95% CI -20.65 to -0.82 nmol/L).

    “participants with lifestyle only had an improved SHBG (MD -10.73, 95% CI -20.65 to -0.82 nmol/L).”
    Quote in the paperSubstantial claim
  • Findingcitation

    In adolescents, metformin was superior to placebo in improving HDL (0.18, 95% CI 0.02-0.47 mmol/L).

    “improving HDL (0.18, 95% CI 0.02-0.47mmol/L) in adolescents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Bridger, 2006, Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome, Arch Pediatr Adolesc Med source

      Not checked in the free run.

  • The quote only partly states this claim. 3
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 23

  • The quote only partly states this claim.

    Findingown data

    In women with PCOS and BMI ≥25, metformin compared to placebo produced a larger reduction in LDL (MD -0.35, 95% CI -0.62 to -0.08), with low certainty.

    “LDL (MD -0.35, 95% CI -0.62 to -0.08) (low certainty)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metformin did not reduce BMI in adults with BMI <25 or in adolescents.

    “However, this effect was not observed in adults with a BMI of <25 kg/m 2 or in adolescents.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Metformin compared to placebo produced a larger reduction in BMI (MD -0.53, 95% CI -0.95 to -0.12 kg/m2), with moderate certainty.

    “the reduction of BMI (MD -0.53, 95% CI -0.95 to -0.12 kg/m 2 )”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In women with PCOS and BMI ≥25, metformin compared to placebo produced a larger reduction in total cholesterol (MD -0.41, 95% CI -0.68 to -0.14 mmol/L), with moderate certainty.

    “total cholesterol (MD -0.41, 95% CI -0.68 to -0.14 mmol/L) (moderate certainty)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metformin has mild gastrointestinal side effects that are generally dose dependent and short-term.

    “Metformin has mild gastrointestinal side effects that are generally dose dependent and short-term.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    This systematic review provides higher certainty evidence for metformin's effects on BMI and confirms benefits on WHR, lipids, and glucose.

    “With this systematic review, we advance knowledge updating the previous systematic review and guidelines 2 to demonstrate higher certainty evidence for effects on BMI, as well as confirming benefits of metformin on WHR, lipids, and glucose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Teede, 2018, Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome, Hum Reprod source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In adults with PCOS, metformin shortens the menstrual cycle and increases the number of menstrual cycles per 6 months (very low certainty).

    “Our meta-analyses showed that adults using metformin experienced shortening of the menstrual cycle and more menstrual cycles per 6 months (very low certainty).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Hyperandrogenism and hyperinsulinemia are associated with reproductive dysfunction such as anovulation in PCOS.

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

    Study design and conductown data

    Risk of bias was assessed using an adapted version of RoB2 and independently cross-checked.

    “The quality appraisal of the included studies, in terms of risk of bias (ROB), was performed by J.M. using an adapted version of RoB2 16 and independently cross-checked by M.F. or S.A.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Sterne, 2019, Rob 2: a revised tool for assessing risk of bias in randomised trials, BMJ source

      Not checked in the free run.

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

    Study design and conductown data

    Full-text screening was performed in duplication.

    “The same authors performed the full-text screening in duplication to determine the final included studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Insulin resistance in PCOS is independent of weight but is exacerbated by excess weight gain.

    “This is independent of weight, but is exacerbated by excess weight gain.7,8”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Stepto, 2013, Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp, Hum Reprod source

      Not checked in the free run.

    • cites [8] Cassar, 2016, Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies, Hum Reprod source

      Not checked in the free run.

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

    Study design and conductown data

    Data extraction was performed by one author and cross-checked by another using a standardized extraction form.

    “Data extraction was performed by J.M. and cross-checked by M.F., using a standardized extraction form (Table SC).”
    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 conductown data

    Two authors independently screened each potential study on title and abstract, with disagreements resolved by discussion.

    “Two authors (J.M., M.F., or S.A.) independently screened each potential study on title and abstract with the use of COVIDENCE.Disagreements were solved by discussion.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study protocol was registered in PROSPERO (CRD42022345640) prior to full-text screening in July 2022.

    “The study protocol was registered prior to full-text screening in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022345640) in July 2022.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For many outcomes such as weight, WHR, and lipids, the certainty of available evidence was low and recommendations were conditional.

    “However, for many outcomes such as weight, WHR, and lipids, the certainty of the available evidence was low and recommendations were conditional.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Teede, 2019, Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: A systematic review with meta-analyses, Clin Endocrinol (Oxf) source

      Not checked in the free run.

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

    Premisecitation

    In a prior systematic review, metformin appeared to lower BMI and decrease insulin resistance compared to placebo in PCOS.

    “In a systematic review, 13 metformin appeared to lower BMI and decrease insulin resistance compared to placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Teede, 2019, Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: A systematic review with meta-analyses, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lifestyle management alone may have limited sustainable efficacy for weight loss in women with PCOS and higher BMI, so additional pharmacological treatment may be needed.

    “While lifestyle management is strongly recommended for weight management, 2,12 for those with higher BMI, sustainable efficacy for weight loss can be limited and additional pharmacological treatment may be needed.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Teede, 2018, Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome, Hum Reprod source

      Not checked in the free run.

    • cites [12] Kataoka, 2017, Weight management interventions in women with and without PCOS: a systematic review, Nutrients source

      Not checked in the free run.

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

    Study design and conductcitation

    The systematic review and meta-analysis was conducted following PRISMA guidelines.

    “This systematic review and meta-analysis build on the previous systematic review 13 and is conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.14,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Moher, 2009, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, BMJ source

      Not checked in the free run.

    • cites [15] Page, 2021, The PRISMA 2020 statement: an updated guideline for reporting systematic reviews, BMJ source

      Not checked in the free run.

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

    Premisecitation

    CRP and PAI-1 are reliable markers of inflammation and sensitive predictors of cardiovascular morbidity.

    “CRP and PAI-1 are reliable markers of inflammation and sensitive predictors of cardiovascular morbidity.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Kelly, 2001, Low grade chronic inflammation in women with polycystic ovarian syndrome, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin suppresses hepatic SHBG secretion and acts on the ovary to promote thecal cell androgen synthesis, increasing circulating free testosterone.

    “Insulin suppresses hepatic SHBG secretion and acts on the ovary to promote thecal cell androgen synthesis 58 with the net effect of increasing circulating free testosterone concentrations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Barbieri, 1988, The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism, Fertil Steril source

      Not checked in the free run.

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

    Premisecitation

    Metformin might reduce weight through appetite regulatory pathways in the brain, leading to decreased food uptake.

    “Studies have suggested that metformin might reduce weight through appetite regulatory pathways in the brain, leading to decreased food uptake.50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Malin, 2014, Effects of metformin on weight loss: potential mechanisms, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

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

    Study design and conductown data

    Publication bias was assessed using funnel plots.

    “Meta-analyses are also presented in forest plots and publication bias was assessed using funnel plots.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin increases insulin sensitivity by inhibiting hepatic glucose production, gluconeogenesis, and lipogenesis, resulting in decreased circulating insulin and glucose.

    “From a mechanistic perspective, metformin is known to increase insulin sensitivity by inhibiting the production of hepatic glucose, as well as inhibiting gluconeogenesis and lipogenesis, resulting in a decrease in circulating insulin and glucose.54”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Rena, 2017, The mechanisms of action of metformin, Diabetologia source

      Not checked in the free run.

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

    Study design and conductcitation

    Each outcome was allocated a certainty of evidence using GRADE, double-checked.

    “Using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) prescribed method and scale, 17 each outcome was allocated as having a high, moderate, low, or very low certainty of evidence.The GRADE assessments were conducted by J.M. and double-checked by M.F. or S.A.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] GRADE working Group

      Not checked in the free run.

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

    Study design and conductown data

    Subgroup analyses were performed by BMI categories <25 and ≥25 kg/m2.

    “We performed subgroup analyses by BMI, categorized as those with BMI < 25 kg/m 2 and those with BMI ≥ 25 kg/m 2 .”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Low SHBG levels are a feature of PCOS and associated comorbidities including type 2 diabetes, insulin resistance, and obesity.

    “Low SHBG levels are a feature of PCOS and associated co-morbidities including type 2 diabetes, insulin resistance, and obesity.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Deswal, 2018, Sex hormone binding globulin—an important biomarker for predicting PCOS risk: A systematic review and meta-analysis, Syst Biol Reprod Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight is a primary concern for women with PCOS because weight gain and obesity exacerbate insulin resistance and increase the risk of type 2 diabetes and cardiometabolic diseases.

    “This is particularly important as weight is a primary concern for women with PCOS 51 because weight gain and obesity exacerbate insulin resistance and increase the risk of type 2 diabetes and cardiometabolic diseases in women with PCOS.52”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Gibson-Helm, 2017, Delayed diagnosis and a lack of information associated with dissatisfaction in women with polycystic ovary syndrome, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [52] Lim, 2013, The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis, Obes Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    This review will directly inform the 2023 International PCOS Evidence-based Guideline.

    “The results and conclusions are derived from International gold-standard evidence synthesis methodologies and will directly inform the 2023 internationally endorsed evidence-based guidelines in PCOS to guide clinical practice, with priorities defined by consumers, key scientific bodies, and experts in the field.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Previous studies suggest the effect of metformin on androgen levels is more pronounced in non-obese women.

    “The ability of metformin to reduce androgen levels in women with hyperandrogenic PCOS has been shown in previous studies, which have also suggested that the effect is more pronounced in non-obese women.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Tang, 2012, Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility, Cochrane Database Syst Rev

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Study design and conductnone given

    The results and conclusions are derived from international gold-standard evidence synthesis methodologies.

    “The results and conclusions are derived from International gold-standard evidence synthesis methodologies and will directly inform the 2023 internationally endorsed evidence-based guidelines in PCOS to guide clinical practice, with priorities defined by consumers, key scientific bodies, and experts in the field.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    This systematic review is the most extensive, up-to-date review investigating the effect of metformin in women with PCOS with or without obesity, including both adults and adolescents.

    “The main strength of this systematic review is that it is the most extensive, up to date review investigating the effect of metformin in women with PCOS with or without obesity, including both adults and adolescents.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    This evidence informed the recommendations in the 2023 International PCOS Evidence-based Guideline.

    “This evidence informed the recommendations in the 2023 International PCOS Evidence-based Guideline, which recommends that health professionals need to inform women and discuss the evidence, possible concerns and side effects of metformin and regulators should be encouraged to consider approval of use of metformin in PCOS.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Metformin has been used largely based on expert opinion to promote improved ovulatory function, increase menstrual cycle regularity and reproductive outcomes in women with PCOS.

    “Metformin has been used largely based on expert opinion to promote improved ovulatory function, increase menstrual cycle regularity and reproductive outcomes in women with PCOS.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Morley, 2017, Metformin therapy for the management of infertility in women with polycystic ovary syndrome: scientific impact paper No. 13, BJOG

      Not checked in the free run.

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

    Study design and conductnone given

    There is an absence of larger studies on women with BMI <25 kg/m2 and adolescents with PCOS.

    “The absence of larger studies on women with BMI <25 kg/m 2 and adolescents with PCOS is a limitation and an area for future research.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Extended-release metformin preparations may decrease gastrointestinal side effects.

    “Extended-release preparations may also decrease the gastrointestinal side effects.2,66”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Teede, 2018, Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome, Hum Reprod source

      Not checked in the free run.

    • cites [66] Domecq, 2013, Adverse effects of the common treatments for polycystic ovary syndrome: a systematic review and meta-analysis, J Clin Endocrinol Metab source

      Not checked in the free run.

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

    Interpretationcitation

    The findings of this review are consistent with previous systematic reviews comparing metformin to placebo with or without lifestyle.

    “These findings are consistent with previous systematic reviews comparing metformin to placebo with or without lifestyle.61,64,65”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Tang, 2012, Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility, Cochrane Database Syst Rev

      Not checked in the free run.

    • cites [64] Legro, 2007, Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome, N Engl J Med source

      Not checked in the free run.

    • cites [65] Misso, 2013, Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis, Hum Reprod Update source

      Not checked in the free run.

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

    Study design and conductreasoning

    ROB and grading assessments were conducted by two authors independently.

    “We acknowledge that critical appraisal is subjective, which is why both ROB and grading assessments were conducted by two authors independently.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Critical appraisal is subjective.
36 of 36

  • The paper relies on this without support.

    The included studies are sufficiently similar in populations and interventions to be pooled in meta-analyses despite differences in metformin doses and treatment durations.

    “Due to study heterogeneity from differences in metformin doses and durations of treatment, a random effects model was used for the meta-analyses.”

  • The paper relies on this without support.

    The search string from the previous review adequately captures all relevant studies through July 2022.

    “For this study, we updated the search from 2017 until seventh July 2022 using the same search string and databases.”

  • The paper relies on this without support.

    Hyperandrogenism and hyperinsulinemia are associated with reproductive dysfunction such as anovulation in PCOS.

    “Hyperandrogenism and hyperinsulinemia are associated with reproductive dysfunction such as anovulation in PCOS.”

  • The authors state this as an assumption.

    Critical appraisal is subjective.

    “We acknowledge that critical appraisal is subjective, which is why both ROB and grading assessments were conducted by two authors independently.”

  • The paper relies on this without support.

    Lifestyle intervention is fundamental in PCOS management.

    “In conclusion, whilst lifestyle intervention is fundamental in PCOS management, those with PCOS should be offered the option of metformin if outcomes align to patient priorities.”

  • The authors state this as an assumption.

    The use of metformin in PCOS is evidence-based but off-label.

    “We acknowledge that the use of metformin in PCOS is evidencebased but off label.”

  • The paper relies on this without support.

    Clinical experience of metformin use in other conditions has revealed that adverse effects can be minimized by starting metformin at a lower dose and titrating upward.

    “Clinical experience of metformin use in other conditions has revealed that adverse effects can be minimized by starting metformin treatment at a lower dose such as 500 mg twice daily followed by weekly 500 mg increments until the maximum dose (2.5 g in adults and 2.0 g in adolescents) is achieved.”
7 of 7

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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.

  • Hirsutism evidence certainty changes from low to moderate

    Minor

    The results describe the certainty for hirsutism as low, while the discussion describes it as moderate.

1 of 1

Cites

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Research works printed but not linked: 1

  1. Morley, 2017, Metformin therapy for the management of infertility in women with polycystic ovary syndrome: scientific impact paper No. 13, BJOG, 124, e306

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Related

Authors
Melin, J., Forslund, M., Alesi, S., Piltonen, T., Romualdi, D., Spritzer, P. M., Tay, C. T., Pena, A., Witchel, S. F., Mousa, A., & Teede, H.
Affiliations
  • University of Helsinki (FI)
  • Monash University (AU)
  • Oulu University Hospital (FI)
  • Agostino Gemelli University Polyclinic (IT)
  • Universidade Federal do Rio Grande do Sul (BR)
  • Discipline of Paediatics, The University of Adelaide and Robinson Research Institute , Adelaide, South Australia 5005 , Australia
  • Children's Hospital of Pittsburgh (US)
  • Monash Medical Centre (AU)
Corresponding author
Melin, Johanna
ORCID
Venue
European Journal of Endocrinology
Publisher
Oxford University Press (OUP)
Published
2023-08
Volume
189
Issue
2
Pages
S38-S64
ISSN
  • 0804-4643 (ISSN-L)
  • 1479-683X
DOI
10.1093/ejendo/lvad098
OpenAlex
W4385564062
Cited by
72
References
64
Citations by year
2026: 27 · 2025: 24 · 2024: 18 · 2023: 3
FWCI
2.92
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Endocrinology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • The Medical Society of Finland and Orion Research foundation
  • Iris foundation and Hjalmar Svensson Foundation
  • National Health and Medical Research Council
  • Royal Australasian College of Physicians Foundation Roger Bartop Research Establishment Fellowship
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
metformin, polycystic ovary syndrome, lifestyle modification, insulin resistance, body mass index, weight loss, fasting blood glucose, lipid profile, gastrointestinal adverse effects, hyperinsulinemia
MeSH terms
Adult, Female, Humans, Hypoglycemic Agents, Insulin Resistance, Life Style, Metformin, Polycystic Ovary Syndrome, Randomized Controlled Trials as Topic

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 2026-10-10.

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

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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